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Publisher: John Wiley and Sons   (Total: 1597 journals)

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Showing 1 - 200 of 1597 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 13, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 67, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 49, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 55, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 177, SJR: 0.101, h-index: 9)
Acta Geologica Sinica (English Edition)     Hybrid Journal   (Followers: 3, SJR: 0.552, h-index: 41)
Acta Neurologica Scandinavica     Hybrid Journal   (Followers: 5, SJR: 1.203, h-index: 74)
Acta Obstetricia et Gynecologica Scandinavica     Hybrid Journal   (Followers: 14, SJR: 1.197, h-index: 81)
Acta Ophthalmologica     Hybrid Journal   (Followers: 7, SJR: 0.112, h-index: 1)
Acta Paediatrica     Hybrid Journal   (Followers: 56, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 6, SJR: 1.69, h-index: 88)
Acta Polymerica     Hybrid Journal   (Followers: 9)
Acta Psychiatrica Scandinavica     Hybrid Journal   (Followers: 37, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 7, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 5)
Addiction     Hybrid Journal   (Followers: 36, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 15, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 26, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 28, SJR: 0.81, h-index: 81)
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Advanced Healthcare Materials     Hybrid Journal   (Followers: 14, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 283, SJR: 9.021, h-index: 345)
Advanced Materials Interfaces     Hybrid Journal   (Followers: 6, SJR: 1.177, h-index: 10)
Advanced Optical Materials     Hybrid Journal   (Followers: 7, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 5)
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Advances in Polymer Technology     Hybrid Journal   (Followers: 14, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 21)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 13)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 11)
African Development Review     Hybrid Journal   (Followers: 33, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 16, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 17, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 11, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 3, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 16, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 45, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 32, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 34, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 50, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 152, SJR: 0.951, h-index: 61)
American Business Law J.     Hybrid Journal   (Followers: 24, SJR: 0.205, h-index: 17)
American Ethnologist     Hybrid Journal   (Followers: 93, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 30, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 35, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 13, SJR: 1.018, h-index: 58)
American J. of Industrial Medicine     Hybrid Journal   (Followers: 16, SJR: 0.993, h-index: 85)
American J. of Medical Genetics Part A     Hybrid Journal   (Followers: 17, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 6, SJR: 2.315, h-index: 79)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 38, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 300, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 14, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 4, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 19, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 10, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 146, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 10, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 20)
Anatomia, Histologia, Embryologia: J. of Veterinary Medicine Series C     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 27)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1, SJR: 0.633, h-index: 24)
Andrologia     Hybrid Journal   (Followers: 2, SJR: 0.528, h-index: 45)
Andrology     Hybrid Journal   (Followers: 2, SJR: 0.979, h-index: 14)
Angewandte Chemie     Hybrid Journal   (Followers: 175)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 238, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 41, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 6, SJR: 0.569, h-index: 24)
Annalen der Physik     Hybrid Journal   (Followers: 5, SJR: 1.46, h-index: 40)
Annals of Anthropological Practice     Partially Free   (Followers: 2, SJR: 0.187, h-index: 5)
Annals of Applied Biology     Hybrid Journal   (Followers: 7, SJR: 0.816, h-index: 56)
Annals of Clinical and Translational Neurology     Open Access   (Followers: 1)
Annals of Gastroenterological Surgery     Open Access  
Annals of Human Genetics     Hybrid Journal   (Followers: 9, SJR: 1.191, h-index: 67)
Annals of Neurology     Hybrid Journal   (Followers: 49, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 1, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 8, SJR: 0.336, h-index: 23)
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5, SJR: 2.389, h-index: 189)
Annual Bulletin of Historical Literature     Hybrid Journal   (Followers: 12)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 26, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 18, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 15)
Anthropology of Consciousness     Hybrid Journal   (Followers: 11, SJR: 0.172, h-index: 5)
Anthropology of Work Review     Hybrid Journal   (Followers: 11, SJR: 0.256, h-index: 5)
Anthropology Today     Hybrid Journal   (Followers: 94, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 54, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 8, SJR: 0.432, h-index: 59)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apmis     Hybrid Journal   (Followers: 1, SJR: 0.855, h-index: 73)
Applied Cognitive Psychology     Hybrid Journal   (Followers: 74, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 170, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 53, SJR: 0.868, h-index: 13)
Applied Stochastic Models in Business and Industry     Hybrid Journal   (Followers: 5, SJR: 0.613, h-index: 24)
Aquaculture Nutrition     Hybrid Journal   (Followers: 12, SJR: 1.025, h-index: 55)
Aquaculture Research     Hybrid Journal   (Followers: 31, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 36, SJR: 1.047, h-index: 57)
Arabian Archaeology and Epigraphy     Hybrid Journal   (Followers: 12, SJR: 0.453, h-index: 11)
Archaeological Prospection     Hybrid Journal   (Followers: 12, SJR: 0.922, h-index: 21)
Archaeology in Oceania     Hybrid Journal   (Followers: 13, SJR: 0.745, h-index: 18)
Archaeometry     Hybrid Journal   (Followers: 31, SJR: 0.809, h-index: 48)
Archeological Papers of The American Anthropological Association     Hybrid Journal   (Followers: 15, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 29, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 3, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 5)
Archives of Insect Biochemistry and Physiology     Hybrid Journal   (SJR: 0.768, h-index: 54)
Area     Hybrid Journal   (Followers: 13, SJR: 0.938, h-index: 57)
Art History     Hybrid Journal   (Followers: 272, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 56, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 29, SJR: 2.256, h-index: 114)
Artificial Organs     Hybrid Journal   (Followers: 1, SJR: 0.872, h-index: 60)
ASHE Higher Education Reports     Hybrid Journal   (Followers: 15)
Asia & the Pacific Policy Studies     Open Access   (Followers: 17)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 329, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (Followers: 1, SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 8, SJR: 0.345, h-index: 20)
Asia-pacific J. of Clinical Oncology     Hybrid Journal   (Followers: 6, SJR: 0.554, h-index: 14)
Asia-Pacific J. of Financial Studies     Hybrid Journal   (SJR: 0.241, h-index: 7)
Asia-Pacific Psychiatry     Hybrid Journal   (Followers: 4, SJR: 0.377, h-index: 7)
Asian Economic J.     Hybrid Journal   (Followers: 8, SJR: 0.234, h-index: 21)
Asian Economic Policy Review     Hybrid Journal   (Followers: 4, SJR: 0.196, h-index: 12)
Asian J. of Control     Hybrid Journal   (SJR: 0.862, h-index: 34)
Asian J. of Endoscopic Surgery     Hybrid Journal   (Followers: 1, SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 6, SJR: 1.443, h-index: 19)
Asian J. of Social Psychology     Hybrid Journal   (Followers: 6, SJR: 0.665, h-index: 37)
Asian Politics and Policy     Hybrid Journal   (Followers: 12, SJR: 0.207, h-index: 7)
Asian Social Work and Policy Review     Hybrid Journal   (Followers: 5, SJR: 0.318, h-index: 5)
Asian-pacific Economic Literature     Hybrid Journal   (Followers: 5, SJR: 0.168, h-index: 15)
Assessment Update     Hybrid Journal   (Followers: 4)
Astronomische Nachrichten     Hybrid Journal   (Followers: 3, SJR: 0.701, h-index: 40)
Atmospheric Science Letters     Open Access   (Followers: 29, SJR: 1.332, h-index: 27)
Austral Ecology     Hybrid Journal   (Followers: 15, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 9, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 8, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 6, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 14, SJR: 0.275, h-index: 28)
Australian Accounting Review     Hybrid Journal   (Followers: 3, SJR: 0.709, h-index: 14)
Australian and New Zealand J. of Family Therapy (ANZJFT)     Hybrid Journal   (Followers: 3, SJR: 0.382, h-index: 12)
Australian and New Zealand J. of Obstetrics and Gynaecology     Hybrid Journal   (Followers: 46, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 13, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 6, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 6, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 31, SJR: 0.23, h-index: 9)
Australian Economic Review     Hybrid Journal   (Followers: 6, SJR: 0.357, h-index: 21)
Australian Endodontic J.     Hybrid Journal   (Followers: 3, SJR: 0.513, h-index: 24)
Australian J. of Agricultural and Resource Economics     Hybrid Journal   (Followers: 3, SJR: 0.765, h-index: 36)
Australian J. of Grape and Wine Research     Hybrid Journal   (Followers: 5, SJR: 0.879, h-index: 56)
Australian J. of Politics & History     Hybrid Journal   (Followers: 15, SJR: 0.203, h-index: 14)
Australian J. of Psychology     Hybrid Journal   (Followers: 18, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 441, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 6, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 75, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 11, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 23, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 38, SJR: 2.126, h-index: 39)
Autonomic & Autacoid Pharmacology     Hybrid Journal   (SJR: 0.371, h-index: 29)
Banks in Insurance Report     Hybrid Journal   (Followers: 1)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 11, SJR: 0.539, h-index: 70)
Basic and Applied Pathology     Open Access   (Followers: 2, SJR: 0.113, h-index: 4)
Basin Research     Hybrid Journal   (Followers: 5, SJR: 1.54, h-index: 60)
Bauphysik     Hybrid Journal   (Followers: 2, SJR: 0.194, h-index: 5)
Bauregelliste A, Bauregelliste B Und Liste C     Hybrid Journal  
Bautechnik     Hybrid Journal   (Followers: 1, SJR: 0.321, h-index: 11)
Behavioral Interventions     Hybrid Journal   (Followers: 10, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 23, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 10, SJR: 0.11, h-index: 5)
Beton- und Stahlbetonbau     Hybrid Journal   (Followers: 2, SJR: 0.493, h-index: 14)
Biochemistry and Molecular Biology Education     Hybrid Journal   (Followers: 6, SJR: 0.311, h-index: 26)
Bioelectromagnetics     Hybrid Journal   (Followers: 1, SJR: 0.568, h-index: 64)
Bioengineering & Translational Medicine     Open Access  
BioEssays     Hybrid Journal   (Followers: 10, SJR: 3.104, h-index: 155)
Bioethics     Hybrid Journal   (Followers: 14, SJR: 0.686, h-index: 39)
Biofuels, Bioproducts and Biorefining     Hybrid Journal   (Followers: 1, SJR: 1.725, h-index: 56)
Biological J. of the Linnean Society     Hybrid Journal   (Followers: 18, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 5, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 41, SJR: 0.12, h-index: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9, SJR: 1.812, h-index: 69)
Biomedical Chromatography     Hybrid Journal   (Followers: 7, SJR: 0.572, h-index: 49)
Biometrical J.     Hybrid Journal   (Followers: 5, SJR: 0.784, h-index: 44)
Biometrics     Hybrid Journal   (Followers: 37, SJR: 1.906, h-index: 96)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10, SJR: 0.715, h-index: 44)
Biopolymers     Hybrid Journal   (Followers: 18, SJR: 1.199, h-index: 104)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 44, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 160, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 15, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 20, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 9, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 38, SJR: 0.763, h-index: 64)
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 2, SJR: 0.727, h-index: 77)
Birth Defects Research Part B: Developmental and Reproductive Toxicology     Hybrid Journal   (Followers: 8, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)

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Journal Cover Addiction Biology
  [SJR: 2.091]   [H-I: 57]   [15 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1355-6215 - ISSN (Online) 1369-1600
   Published by John Wiley and Sons Homepage  [1597 journals]
  • Genome-wide association study in Finnish twins highlights the connection
           between nicotine addiction and neurotrophin signaling pathway
    • Authors: Jenni Hällfors; Teemu Palviainen, Ida Surakka, Richa Gupta, Jadwiga Buchwald, Anu Raevuori, Samuli Ripatti, Tellervo Korhonen, Pekka Jousilahti, Pamela A.F. Madden, Jaakko Kaprio, Anu Loukola
      Abstract: The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel. We analyzed three measures of nicotine addiction—smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome-wide significant SNPs for their functional potential. First, we detected genome-wide significant association on 16p12 with smoking quantity (P = 8.5 × 10−9), near CLEC19A. The lead-SNP stands 22 kb from a binding site for NF-κB transcription factors, which play a role in the neurotrophin signaling pathway. However, the signal was not replicated in an independent Finnish population-based sample, FINRISK (n = 6763). Second, nicotine withdrawal showed association on 2q21 in an intron of TMEM163 (P = 2.1 × 10−9), and on 11p15 (P = 6.6 × 10−8) in an intron of AP2A2, and P = 4.2 × 10−7 for a missense variant in MUC6, both involved in the neurotrophin signaling pathway). Third, association was detected on 3p22.3 for maximum number of cigarettes smoked per day (P = 3.1 × 10−8) near STAC. Associating CLEC19A and TMEM163 SNPs were annotated to influence gene expression or methylation. The neurotrophin signaling pathway has previously been associated with smoking behavior. Our findings further support the role in nicotine addiction.We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. We detected a genome-wide significant association on 16p12 with smoking quantity (P = 8.5 × 10−9), near CLEC19A. The lead-SNP stands 22 kb from a binding site for NF-κB transcription factors, which play a role in the neurotrophin signaling pathway. The neurotrophin signaling pathway has previously been associated with smoking behavior, and our findings further support its role in nicotine addiction.
      PubDate: 2018-03-13T03:16:33.127489-05:
      DOI: 10.1111/adb.12618
  • Evidence of subgroups in smokers as revealed in clinical measures and
           evaluated by neuroimaging data: a preliminary study
    • Authors: Xiaoyu Ding; Betty Jo Salmeron, Jamei Wang, Yihong Yang, Elliot A. Stein, Thomas J. Ross
      Abstract: To date, fractionation of the nicotine addiction phenotype has been limited to that based primarily on characteristics of cigarette use, although it is widely appreciated that a variety of individual factors are associated with tobacco use disorder. Identifying subtypes of tobacco use disorder based on such factors may lead to better understanding of potential treatment targets, individualize treatments and improve outcomes. In this preliminary study, to identify potential subgroups, we applied hierarchical clustering to a broad range of assessments measuring personality, IQ and psychiatric symptoms, as well as various environmental and experiential characteristics from 102 otherwise healthy cigarette smokers. The identified subgroups were further compared on various resting-state fMRI measures from a subset (N = 65) of individuals who also underwent resting-state fMRI scanning. The clustering dendrogram indicated that smokers can be divided into three subgroups. Each subgroup had unique clinical assessment characteristics. The division yielded imaging differences between subgroups in the supplementary motor area/middle cingulate cortex and the cuneus. Regression analyses showed that amplitude of low frequency fluctuations in the supplementary motor area/middle cingulate cortex differed between groups and were negatively correlated with the Toronto Alexithymia Scale subscale Difficulty Describing Feelings.We applied hierarchical clustering to a broad range of clinical measures to identify subtypes of tobacco use disorder. Smokers can be divided into three subgroups with unique clinical assessment characteristics in each subgroup. The division yielded imaging differences between subgroups in the supplementary motor area/middle cingulate cortex and the cuneus.
      PubDate: 2018-03-08T01:15:36.080568-05:
      DOI: 10.1111/adb.12620
  • Drinking despite adversity: behavioral evidence for a head down and push
           strategy of conflict-resistant alcohol drinking in rats
    • Authors: David Darevsky; Thomas Michael Gill, Katherine Rose Vitale, Bing Hu, Scott Andrew Wegner, Frederic Woodward Hopf
      Abstract: Compulsive alcohol drinking, where intake persists regardless of adverse consequences, plays a major role in the substantial costs of alcohol use disorder. However, the processes that promote aversion-resistant drinking remain poorly understood. Compulsion-like responding has been considered automatic and reflexive and also to involve higher motivation, since drinking persists despite adversity. Thus, we used lickometry, where microstructural behavioral changes can reflect altered motivation, to test whether conflict-resistant intake [quinine-alcohol (QuiA)] reflected greater automaticity or motivation relative to alcohol-only drinking (Alc). Front-loading during QuiA and Alc suggested incentive to drink in both. However, the relationship between total licking and intake was less variable during QuiA, as was lick volume, without changes in average responding. QuiA bout organization was also less variable, with fewer licks outside of bouts (stray licks) and fewer gaps within bouts. Interestingly, QuiA avoidance of stray licking continued into short bouts, with fewer short and more medium-length bouts, which was striking given their minor impact on intake. Instead, more effort at bout onset could allow short bouts to persist longer. Indeed, while QuiA licking was overall faster, QuiA bouts were especially fast at bout initiation. However, few QuiA changes individually predicted greater intake, perhaps suggesting an overarching strategy during aversion-resistant responding. Thus, our results indicate that aversion-resistant intake exhibited less variability, where increased automaticity could decrease need for awareness, and stronger bout initiation, which might prolong responding despite adversity. This may reflect a collective strategy, which we call Head Down and Push responding that facilitates conflict-resistant, compulsion-like intake.Compulsion-like alcohol drinking, where intake persists despite negative consequences, has been considered to reflect more automatic and habitual responding and also to exhibit a higher motivation that is required to maintain punishment-resistant intake. In fact, compulsion-like drinking in rats overall exhibits less variability and greater drive relative to alcohol-only intake. Thus, compulsion-like intake may involve a strategy which reduces the need for awareness during control of licking and allows intake to occur at all despite adverse consequences.
      PubDate: 2018-03-08T00:55:58.357596-05:
      DOI: 10.1111/adb.12608
  • Ago2 and Dicer1 are involved in METH-induced locomotor sensitization in
           mice via biogenesis of miRNA
    • Authors: Dan Liu; Li Zhu, Tong Ni, Fang-lin Guan, Yan-jiong Chen, Dong-liang Ma, Eyleen L.K. Goh, Teng Chen
      Abstract: microRNA (miRNA) play important roles in drug addiction and act as a post-transcriptional regulator of gene expression. We previously reported extensive downregulation of miRNAs in the nucleus accumbens (NAc) of methamphetamine (METH)-sensitized mice. However, the regulatory mechanism of this METH-induced downregulation of miRNAs has yet to be elucidated. Thus, we examined METH-induced changes in the expression of miRNAs and their precursors, as well as the expression levels of mRNA and the proteins involved in miRNA biogenesis such as Dicer1 and Ago2, in the nucleus accumbens of METH-induced locomotor sensitized mice. miRNAs and Ago2 were significantly downregulated, while the expression of miRNA precursors remained unchanged or upregulated, which suggests that the downregulation of miRNAs was likely due to a reduction in Ago2-mediated splicing but unlikely to be regulated at the transcription level. Interestingly, the expression level of Dicer1, which is a potential target of METH-induced decreased miRNAs, such as miR-124, miR-212 and miR-29b, was significantly increased. In conclusion, this study indicates that miRNA biogenesis (such as Ago2 and Dicer1) and their miRNA products may have a role in the development of METH addiction.miRNA biogenesis (Ago2 and Dicer1) and their miRNA products may have a role in methamphetamine (METH) addiction. miRNAs and Ago2 were significantly down-regulated, while pre-miRNA remained unchanged or up-regulated, which suggests that the down-regulation of miRNAs was likely due to a reduction in Ago2-mediated splicing. Dicer1 was significantly increased and was a potential target of METH-induced decreased miRNAs such as miR-124, miR-212 and miR-29b. Our study revealed a homeostasis mechanism between miRNA biogenesis and its interacting miRNAs in response to METH.
      PubDate: 2018-03-08T00:45:37.621228-05:
      DOI: 10.1111/adb.12616
  • Enhanced neuronal and blunted hemodynamic reactivity to cocaine in the
           prefrontal cortex following extended cocaine access: optical imaging study
           in anesthetized rats
    • Authors: Craig P. Allen; Kicheon Park, Ang Li, Nora D. Volkow, George F. Koob, Yingtian Pan, Xiu-Ti Hu, Congwu Du
      Abstract: Cocaine addiction is associated with dysfunction of the prefrontal cortex (PFC), which facilitates relapse and compulsive drug taking. To assess if cocaine's effects on both neuronal and vascular activity contribute to PFC dysfunction, we used optical coherence tomography and multi-wavelength laser speckle to measure vascularization and hemodynamics and used GCaMP6f to monitor intracellular Ca2+ levels ([Ca2+]in) as a marker of neuronal activity. Rats were given short (1 hour; ShA) or long (6 hours; LgA) access cocaine self-administration. As expected, LgA but not ShA rats escalated cocaine intake. In naïve rats, acute cocaine decreased oxygenated hemoglobin, increased deoxygenated hemoglobin and reduced cerebral blood flow in PFC, likely due to cocaine-induced vasoconstriction. ShA rats showed enhanced hemodynamic response and slower recovery after cocaine, versus naïve. LgA rats showed a blunted hemodynamic response, but an enhanced PFC neuronal [Ca2+]in increase after cocaine challenge associated with drug intake. Both ShA and LgA groups had higher vessel density, indicative of angiogenesis, presumably to compensate for cocaine's vasoconstricting effects. Cocaine self-administration modified the PFC cerebrovascular responses enhancing it in ShA and attenuating it in LgA animals. In contrast, LgA but not ShA animals showed sensitized neuronal reactivity to acute cocaine in the PFC. The opposite changes in hemodynamics (decreased) and neuronal responses (enhanced) in LgA rats indicate that these constitute distinct effects and suggest that the neuronal and not the vascular effects are associated with escalation of cocaine intake in addiction whereas its vascular effect in PFC might contribute to cognitive deficits that increase vulnerability to relapse.Using optical imaging in the prefrontal cortex (a), we found that a history of long access cocaine self-administration caused a blunted hemodynamic (b) and an enhanced neuronal (c) response to a cocaine challenge. This dissociation between vascular and neuronal adaptations may contribute to the escalation of drug intake and the prefrontal cortex dysfunction observed in cocaine abusers.
      PubDate: 2018-03-05T06:02:41.361209-05:
      DOI: 10.1111/adb.12615
  • Preclinical evidence for combining the 5-HT2C receptor agonist lorcaserin
           and varenicline as a treatment for nicotine dependence
    • Authors: Paul J. Fletcher; Zhaoxia Li, Leo B. Silenieks, Cam MacMillan, Ines DeLannoy, Guy A. Higgins
      Abstract: Varenicline, a nicotinic acetylcholine receptor partial agonist, is used to treat nicotine dependence. Lorcaserin, a 5-HT2C receptor agonist has been approved in some countries to treat obesity. Based on preclinical and preliminary clinical evidence, lorcaserin may have potential to treat nicotine dependence. These experiments examined in rats the effects of combining varenicline (0.5 or 1 mg/kg) and lorcaserin (0.3, 0.6 and 1 mg/kg) on nicotine self-administration, reinstatement of nicotine seeking, responding for food and impulsive action. Both drugs alone reduced nicotine self-administration. Combining varenicline and 0.6 mg/kg lorcaserin reduced responding to a greater extent than either drug alone. In a relapse model, extinguished nicotine seeking was reinstated by a priming injection of nicotine and nicotine-associated cues. Reinstatement was reduced by varenicline (1 mg/kg) and by lorcaserin (0.3 mg/kg). Combining lorcaserin (0.3 mg/kg) with varenicline (0.5 or 1 mg/kg) reduced reinstatement to a greater degree than either drug alone. Both drugs had minimal effects on responding for food, alone or in combination. In the five-choice serial reaction time test, varenicline (0.5 or 1 mg/kg) increased impulsivity, measured as increased premature responding. This effect was reduced by lorcaserin (0.3 mg/kg). Plasma levels of varenicline or lorcaserin were not altered by co-administration of the other drug. Varenicline and lorcaserin have additive effects on nicotine self-administration, and on nicotine seeking. Lorcaserin prevents impulsivity induced by varenicline. This pattern of effects suggests that co-administration of varenicline and lorcaserin has potential as a treatment for nicotine dependence that may exceed the value of either drug alone.We investigated the effects of the 5-HT2C receptor agonist lorcaserin and the nicotinic partial agonist varenicline on behaviours related to nicotine addiction. Lorcaserin and varenicline reduced nicotine self-administration and reinstatement in an additive manner. Lorcaserin blocked the effect of varenicline to increase impulsivity. The results suggest that combining lorcaserin and varenicline should be considered as a treatment for nicotine dependence.
      PubDate: 2018-03-02T03:52:21.007028-05:
      DOI: 10.1111/adb.12602
  • Pharmacogenetics of Dopamine β-Hydroxylase in cocaine dependence
           therapy with doxazosin
    • Authors: Xuefeng Zhang; David A. Nielsen, Coreen B. Domingo, Daryl I. Shorter, Ellen M. Nielsen, Thomas R. Kosten
      Abstract: The α1-adrenergic antagonist, doxazosin, has improved cocaine use disorder (CUD) presumably by blocking norepinephrine (NE) stimulation and reward from cocaine-induced NE increases. If the NE levels for release were lower, then doxazosin might more readily block this NE stimulation and be more effective. The NE available for release can be lower through a genetic polymorphism in dopamine β-hydroxylase (DBH) (C-1021T, rs1611115), which reduces DβH's conversion of dopamine to NE. We hypothesize that doxazosin would be more effective in CUD patients who have these genetically lower DβH levels. This 12-week, double-blind, randomized, placebo-controlled trial included 76 CUD patients: 49 with higher DβH levels from the DBH CC genotype and 27 with lower DβH levels from T-allele carriers (CT or TT). Patients were randomized to doxazosin (8 mg/day, N = 47) or placebo (N = 29) and followed with thrice weekly urine toxicology and once weekly cognitive behavioral psychotherapy. Cocaine use was reduced at a higher rate among patients in the doxazosin than in the placebo arm. We found significantly lower cocaine use rates among patients carrying the T-allele (CT/TT) than the CC genotype. The percentage of cocaine positive urines was reduced by 41 percent from baseline in the CT/TT group with low DβH and NE levels, as compared with no net reduction in the CC genotype group with normal DβH and NE levels. The DBH polymorphism appears play an important role in CUD patients' response to doxazosin treatment, supporting a pharmacogenetic association and potential application for personalized medicine.The dopamine β hydroxylase (DβH) is the key enzyme to control the conversion of dopamine to norepinephrine (NE). The genetic polymorphism in DBH (C-1021T) is correlated with lower DβH enzyme and NE levels in the CT/TT genotype. The α1adrenergic antagonist, doxazosin, significantly reduces cocaine use in this population by blocking norepinephrine stimulation and reward from cocaine-induced norepinephrine increases. Less NE is easier to block by doxazosin and then easier to stop reinforcement from cocaine.
      PubDate: 2018-03-02T03:35:54.471928-05:
      DOI: 10.1111/adb.12611
  • The monoamine stabilizer (−)-OSU6162 prevents the alcohol deprivation
           effect and improves motor impulsive behavior in rats
    • Authors: Ida Fredriksson; Malin Wirf, Pia Steensland
      Abstract: Alcohol craving, in combination with impaired impulse control, often leads to relapse. The dopamine system mediates the rewarding properties of alcohol but is also involved in regulating impulsive behavior. The monoamine stabilizer (−)-OSU6162 (OSU6162) has the ability to stabilize dopamine activity depending on the prevailing dopaminergic tone and may therefore normalize the dopaminergic transmission regulating both alcohol use disorder and impulsivity. We have recently showed that OSU6162 attenuates voluntary alcohol consumption, operant alcohol self-administration, alcohol withdrawal symptoms and cue-induced reinstatement of alcohol seeking in rats. Here, we evaluated OSU6162's effects on motor impulsivity in Wistar rats that had voluntarily consumed alcohol or water for 10 weeks. The five-choice serial reaction time task was used to measure motor impulsivity, and a prolonged waiting period (changed from 5 to 7 seconds) was applied to induce premature responses. OSU6162-testing was conducted twice a week (Tuesdays and Fridays), every other week with regular baseline training sessions in between. We also tested OSU6162's effects on the alcohol deprivation effect in long-term alcohol drinking Wistar rats. The results showed that OSU6162 (30 mg/kg) pre-treatment significantly improved motor impulsivity in the five-choice serial reaction time task in both alcohol and alcohol-naïve rats. Moreover, OSU6162 (30 mg/kg) pre-treatment prevented the alcohol deprivation effect, i.e. relapse-like drinking behavior after a forced period of abstinence in long-term drinking rats. In conclusion, our results provide further support for OSU6162 as a novel treatment for alcohol use disorder. The results further indicate that improvement of motor impulse control might be one mechanism behind OSU6162's ability to attenuate alcohol-mediated behaviors.A main problem in the treatment of alcohol use disorder (AUD) is the long-lasting vulnerability to relapse. Impaired impulse control, often seen in AUD individuals, contribute to relapse to alcohol drinking. Here, we showed that the monoamine stabilizer OSU6162 improved motor impulsivity (i.e. decreased premature responses) in both alcohol-naive and alcohol drinking rats as measured with the five-choice serial reaction time task. These results provide further support for the potential of OSU6162 as a novel medication for AUD.
      PubDate: 2018-02-26T05:36:02.707352-05:
      DOI: 10.1111/adb.12613
  • Not all smokers appear to seek nicotine for the same reasons: implications
           for preclinical research in nicotine dependence
    • Authors: Vernon Garcia-Rivas; Véronique Deroche-Gamonet
      Abstract: Tobacco use leads to 6 million deaths every year due to severe long-lasting diseases. The main component of tobacco, nicotine, is recognized as one of the most addictive drugs, making smoking cessation difficult, even when 70 percent of smokers wish to do so. Clinical and preclinical studies have demonstrated consistently that nicotine seeking is a complex behavior involving various psychopharmacological mechanisms. Evidence supports that the population of smokers is heterogeneous, particularly as regards the breadth of motives that determine the urge to smoke. Here, we review converging psychological, genetic and neurobiological data from clinical and preclinical studies supporting that the mechanisms controlling nicotine seeking may vary from individual to individual. It appears timely that basic neuroscience integrates this heterogeneity to refine our understanding of the neurobiology of nicotine seeking, as tremendous progress has been made in modeling the various psychopharmacological mechanisms driving nicotine seeking in rodents. For a better understanding of the mechanisms that drive nicotine seeking, we emphasize the need for individual-based research strategies in which nicotine seeking, and eventually treatment efficacy, are determined while taking into account individual variations in the mechanisms of nicotine seeking.
      PubDate: 2018-02-26T05:35:27.800498-05:
      DOI: 10.1111/adb.12607
  • Lysophosphatidic acid-induced increase in adult hippocampal neurogenesis
           facilitates the forgetting of cocaine-contextual memory
    • Authors: David Ladrón de Guevara-Miranda; Román Darío Moreno-Fernández, Sara Gil-Rodríguez, Cristina Rosell-Valle, Guillermo Estivill-Torrús, Antonia Serrano, Francisco J. Pavón, Fernando Rodríguez de Fonseca, Luis J. Santín, Estela Castilla-Ortega
      Abstract: Erasing memories of cocaine–stimuli associations might have important clinical implications for addiction therapy. Stimulating hippocampal plasticity by enhancing adult hippocampal neurogenesis (AHN) is a promising strategy because the addition of new neurons may not only facilitate new learning but also modify previous connections and weaken retrograde memories. To investigate whether increasing AHN prompted the forgetting of previous contextual cocaine associations, mice trained in a cocaine-induced conditioned place preference (CPP) paradigm were administered chronic intracerebroventricular infusions of lysophosphatidic acid (LPA, an endogenous lysophospholipid with pro-neurogenic actions), ki16425 (an LPA1/3 receptor antagonist) or a vehicle solution, and they were tested 23 days later for CPP retention and extinction. The results of immunohistochemical experiments showed that the LPA-treated mice exhibited reduced long-term CPP retention and an approximately twofold increase in the number of adult-born hippocampal cells that differentiated into mature neurons. Importantly, mediation analyses confirmed a causal role of AHN in reducing CPP maintenance. In contrast, the ki16425-treated mice displayed aberrant responses, with initially decreased CPP retention that progressively increased across the extinction sessions, leading to no effect on AHN. The pharmacological treatments did not affect locomotion or general exploratory or anxiety-like responses. In a second experiment, normal and LPA1-receptor-deficient mice were acutely infused with LPA, which revealed that LPA1-mediated signaling was required for LPA-induced proliferative actions. These results suggest that the LPA/LPA1 pathway acts as a potent in vivo modulator of AHN and highlight the potential usefulness of pro-AHN strategies to treat aberrant cognition in those addicted to cocaine.Mice trained in a cocaine-induced conditioned place preference (CPP) paradigm received intracerebroventricular infusions of lysophosphatidic acid (LPA), LPA1/3 receptor antagonist ki16425 or vehicle solution, and they were tested later for CPP retention and extinction. As a main result, the LPA-induced increase of AHN weakened the long-term retention of the CPP. Our findings highlight the role of LPA as an in vivo modulator of AHN and suggest the potential usefulness of pro-AHN strategies to treat the maladaptive cognition in cocaine users.
      PubDate: 2018-02-26T05:30:39.065982-05:
      DOI: 10.1111/adb.12612
  • Stress augments the rewarding memory of cocaine via the activation of
           brainstem-reward circuitry
    • Authors: Fumiya Shinohara; Yuta Asaoka, Hironori Kamii, Masabumi Minami, Katsuyuki Kaneda
      Abstract: Effects of stress on the reward system are well established in the literature. Although previous studies have revealed that stress can reinstate extinguished addictive behaviors related to cocaine, the effects of stress on the rewarding memory of cocaine are not fully understood. Here, we provide evidence that stress potentiates the expression of rewarding memory of cocaine via the activation of brainstem-reward circuitry using a cocaine-induced conditioned place preference (CPP) paradigm combined with restraint stress in rats. The rats exposed to 30-minute restraint stress immediately before posttest exhibited significantly larger CPP scores compared with non-stressed rats. Intra-laterodorsal tegmental nucleus (LDT) microinjection of a β or α2 adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. Consistent with this observation, intra-LDT microinjection of a β or α2 adrenoceptor agonist before posttest increased cocaine CPP. Additionally, intra-ventral tegmental area (VTA) microinjection of antagonists for the muscarinic acetylcholine, nicotinic acetylcholine or glutamate receptors attenuated the stress-induced enhancement of cocaine CPP. Finally, intra-medial prefrontal cortex (mPFC) microinjection of a D1 receptor antagonist also reduced the stress-induced enhancement of cocaine CPP. These findings suggest a mechanism wherein the LDT is activated by noradrenergic input from the locus coeruleus, leading to the activation of VTA dopamine neurons via both cholinergic and glutamatergic transmission and the subsequent excitation of the mPFC to enhance the memory of cocaine-induced reward value.By combining a cocaine-induced conditioned place preference paradigm with restraint stress, to which rats were exposed immediately before posttest, we provide evidence that stress potentiates the expression of rewarding memory of cocaine via the activation of brainstem-reward circuitry. Intracranial microinjections revealed that under the stress condition, the laterodorsal tegmental nucleus is activated by noradrenergic input from the locus coeruleus via β and α2 adrenoceptors, leading to the activation of ventral tegmental area dopamine neurons through both cholinergic and glutamatergic transmissions. Subsequently, the medial prefrontal cortex is excited by D1 receptor stimulation, resulting in the enhancement of the cocaine-induced rewarding memory.
      PubDate: 2018-02-26T05:15:41.427557-05:
      DOI: 10.1111/adb.12617
  • DRD2 promoter methylation and measures of alcohol reward: functional
           activation of reward circuits and clinical severity
    • Authors: L. Cinnamon Bidwell; Hollis C. Karoly, Rachel E. Thayer, Eric D. Claus, Angela D. Bryan, Barbara J. Weiland, Sophie YorkWilliams, Kent E. Hutchison
      Abstract: Studies have identified strong associations between D2 receptor binding potential and neural responses to rewarding stimuli and substance use. Thus, D2 receptor perturbations are central to theoretical models of the pathophysiology of substance dependence, and epigenetic changes may represent one of the fundamental molecular mechanisms impacting the effects of alcohol exposure on the brain. We hypothesized that epigenetic alterations in the promoter region of the dopamine D2 receptor (DRD2) gene would be associated with cue-elicited activation of neural reward regions, as well as severity of alcohol use behavior. The current study leveraged functional neuroimaging (fMRI) during an alcohol reward paradigm (n = 383) to test associations among DRD2 promoter methylation in peripheral tissue, signal change in the striatum during the presentation of alcohol cues, and severity of alcohol use disorder (AUD). Controlling for age, DRD2 promoter methylation was positively associated with responses to alcohol cues in the right accumbens (partial r = 0.144, P = 0.005), left putamen (partial r = 0.133, P = 0.009), right putamen (partial r = 0.106, P = 0.039), left caudate (partial r = 0.117, P = 0.022), and right caudate (partial r = 0.133, P = 0.009), suggesting that DRD2 methylation was positively associated with robust activation in the striatum in response to reward cues. DRD2 methylation was also positively associated with clinical metrics of AUD severity. Specifically, controlling for age, DRD2 methylation was associated with Alcohol Use Disorders Identification Test total (partial r = 0.140, P = 0.002); Impaired Control Scale total (partial r = 0.097, P = 0.044) and Alcohol Dependence Scale total (partial r = 0.152, P = 0.001). Thus, DRD2 methylation may be a critical mechanism linking D2 receptors with functional striatal brain changes and clinical severity among alcohol users.D2 receptor perturbations are central to theoretical models of alcohol use disorder, and D2 receptor gene (DRD2) epigenetic changes may represent one of the fundamental molecular mechanisms impacting the effect of alcohol exposure on the brain. Leveraging functional neuroimaging during an alcohol reward paradigm in a large sample (n = 383), associations were shown among DRD2 promoter methylation, signal change in the striatum during the presentation of alcohol cues, and the severity of alcohol use disorder.
      PubDate: 2018-02-21T04:10:53.811677-05:
      DOI: 10.1111/adb.12614
  • Effects of alcohol intoxication on self-reported drinking patterns,
           expectancies, motives and personality: a randomized controlled
           experimental study
    • Authors: Sören Kuitunen-Paul; Elisabeth Obst, Ruth Schmidt, Christian Sommer, Paula T. Kuitunen, Hans-Ulrich Wittchen, Ulrich S. Zimmermann
      Abstract: Alcohol intoxication may affect self-reports of alcohol use and related constructs, such as impulsivity and dependence symptoms. Improved knowledge about potential systematic reporting biases induced by alcohol, e.g. through disinhibition, may be relevant for the assessment of intoxicated individuals both in clinical routine and research. We therefore randomly assigned 54 socially drinking males aged 18 to 19 without lifetime diagnosis of DSM-IV alcohol dependence to one of two experimental arms: either placebo infusion at day 1 and alcohol infusion at day 2, or vice versa. The lab-based intravenous alcohol infusion produced a constant blood alcohol level of 0.08 percent. On each day, participants completed the Alcohol Use Disorders Identification Test, as well as other questionnaires on alcohol expectancies, drinking motives and substance use-related temperament traits. We found that alcohol significantly increased self-reported expectancies (tension reduction) and motives (conformity; η2 = .16–.23), but we observed no effect of sequence, i.e. alcohol first versus placebo first (Pcorr ≥ .118). High baseline alcohol expectancies did not moderate alcohol effects (Pcorr ≥ .462). We conclude that moderate alcohol intoxication might not generally affect the reliability of self-reported alcohol use, alcohol use problems and psychological concepts related to drinking behavior in young males without alcohol dependence. Future studies could examine larger, less selective and clinical samples for possible alcohol effects on self-report measures related to alcohol consumption.To examine the effects of alcohol on self-reported alcohol consumption, alcohol expectancies, drinking motives and substance use-related temperament traits, we tested 54 healthy socially drinking males aged 18 to 19 in a placebo-controlled cross-over design. On 2 days, participants either received an alcohol infusion (0.08 percent) or placebo infusion. Besides small alcohol-induced increases in self-reported expectancies of tension reduction and conformity motives, we found no alcohol effects on self-reports of alcohol consumption and relevant psychological constructs.
      PubDate: 2018-02-19T02:20:27.159956-05:
      DOI: 10.1111/adb.12604
  • Time-dependent regional brain distribution of methadone and naltrexone in
           the treatment of opioid addiction
    • Authors: Belin G. Teklezgi; Annapurna Pamreddy, Sooraj Baijnath, Hendrik G. Kruger, Tricia Naicker, Nirmala D. Gopal, Thavendran Govender
      Abstract: Opioid addiction is a serious public health concern with severe health and social implications; therefore, extensive therapeutic efforts are required to keep users drug free. The two main pharmacological interventions, in the treatment of addiction, involve management with methadone an mu (μ)-opioid agonist and treatment with naltrexone, μ-opioid, kappa (κ)-opioid and delta (δ)-opioid antagonist. MET and NAL are believed to help individuals to derive maximum benefit from treatment and undergo a full recovery. The aim of this study was to determine the localization and distribution of MET and NAL, over a 24-hour period in rodent brain, in order to investigate the differences in their respective regional brain distributions. This would provide a better understanding of the role of each individual drug in the treatment of addiction, especially NAL, whose efficacy is controversial. Tissue distribution was determined by using mass spectrometric imaging (MSI), in combination with quantification via liquid chromatography tandem mass spectrometry. MSI image analysis showed that MET was highly localized in the striatal and hippocampal regions, including the nucleus caudate, putamen and the upper cortex. NAL was distributed with high intensities in the mesocorticolimbic system including areas of the cortex, caudate putamen and ventral pallidum regions. Our results demonstrate that MET and NAL are highly localized in the brain regions with a high density of μ-receptors, the primary sites of heroin binding. These areas are strongly implicated in the development of addiction and are the major pathways that mediate brain stimulation during reward.MSI analysis showed that MET and NAL are highly localized in the brain regions with a high density of MU-opioid receptors, the primary sites of heroin binding. MET was highly localized in the striatal and hippocampal regions, including the nucleus caudate, putamen and the upper cortex. NAL was distributed with high intensities in the mesocorticolimbic system including areas of the cortex, caudate putamen and ventral pallidum regions. These areas are involved in the development of addiction and are the major pathways that mediate brain stimulation during reward.
      PubDate: 2018-02-14T02:40:04.794983-05:
      DOI: 10.1111/adb.12609
  • Medial habenula cholinergic signaling regulates cocaine-associated
           relapse-like behavior
    • Authors: Alberto J. López; Yousheng Jia, André O. White, Janine L. Kwapis, Monica Espinoza, Philip Hwang, Rianne Campbell, Yasaman Alaghband, Om Chitnis, Dina P. Matheos, Gary Lynch, Marcelo A. Wood
      Abstract: Propensity to relapse, even following long periods of abstinence, is a key feature in substance use disorders. Relapse and relapse-like behaviors are known to be induced, in part, by re-exposure to drug-associated cues. Yet, while many critical nodes in the neural circuitry contributing to relapse have been identified and studied, a full description of the networks driving reinstatement of drug-seeking behaviors is lacking. One area that may provide further insight to the mechanisms of relapse is the habenula complex, an epithalamic region composed of lateral and medial (MHb) substructures, each with unique cell and target populations. Although well conserved across vertebrate species, the functions of the MHb are not well understood. Recent research has demonstrated that the MHb regulates nicotine aversion and withdrawal. However, it remains undetermined whether MHb function is limited to nicotine and aversive stimuli or if MHb circuit regulates responses to other drugs of abuse. Advances in circuit-level manipulations now allow for cell-type and temporally specific manipulations during behavior, specifically in spatially restrictive brain regions, such as the MHb. In this study, we focus on the response of the MHb to reinstatement of cocaine-associated behavior, demonstrating that cocaine-primed reinstatement of conditioned place preference engages habenula circuitry. Using chemogenetics, we demonstrate that MHb activity is sufficient to induce reinstatement behavior. Together, these data identify the MHb as a key hub in the circuitry underlying reinstatement and may serve as a target for regulating relapse-like behaviors.The medial habenula is a region typically regarded as a mediator of aversion, anxiety-like behaviors, and the aversive properties of nicotine. Here, we demonstrate that the medial habenula is engaged by reinstatement of cocaine-associated behavior. Moreover, we show that chemogenetic activation of the cholinergic habenula population induces reinstatement of cocaine CPP.
      PubDate: 2018-02-12T01:21:01.63334-05:0
      DOI: 10.1111/adb.12605
  • Sex differences in binge-like EtOH drinking, corticotropin-releasing
           hormone and corticosterone: effects of β-endorphin
    • Authors: Todd B. Nentwig; Diane E. Wilson, Erin M. Rhinehart, Judith E. Grisel
      Abstract: Binge drinking is an increasingly common pattern of risky use associated with numerous health problems, including alcohol use disorders. Because low basal plasma levels of β-endorphin (β-E) and an increased β-E response to alcohol are evident in genetically at-risk human populations, this peptide is thought to contribute to the susceptibility for disordered drinking. Animal models suggest that the effect of β-E on consumption may be sex-dependent. Here, we studied binge-like EtOH consumption in transgenic mice possessing varying levels of β-E: wild-type controls with 100% of the peptide (β-E +/+), heterozygous mice constitutively modified to possess 50% of wild-type levels (β-E +/−) and mice entirely lacking the capacity to synthesize β-E (−/−). These three genotypes and both sexes were evaluated in a 4-day, two-bottle choice, drinking in the dark paradigm with limited access to 20% EtOH. β-E deficiency determined sexually divergent patterns of drinking in that β-E −/− female mice drank more than their wild-type counterparts, an effect not observed in male mice. β-E −/− female mice also displayed elevated basal anxiety, plasma corticosterone and corticotropin-releasing hormone mRNA in the extended amygdala, and all of these were normalized by EtOH self-administration. These data suggest that a heightened risk for excessive EtOH consumption in female mice is related to the drug's ability to ameliorate an overactive anxiety/stress-like state. Taken together, our study highlights a critical impact of sex on neuropeptide regulation of EtOH consumption.Sensitivity to alcohol's stress relieving effects plays a critical role in susceptibility toward excessive drinking and alcohol use disorders. b-endorphin deficiency results in sex-specific alterations in brain stress systems, and enhanced alcohol consumption in female, but not male, mice. Females with low b-endorphin may represent a population with increased risk for drinking. Overall, our study suggests that b-endorphin acts to buffer brain stress systems and may safeguard against excessive drinking driven by alcohol's negative reinforcing properties.
      PubDate: 2018-02-08T23:15:30.560831-05:
      DOI: 10.1111/adb.12610
  • Functional effects of synthetic cannabinoids versus Δ9-THC in mice on
           body temperature, nociceptive threshold, anxiety, cognition,
           locomotor/exploratory parameters and depression
    • Authors: Shaul Schreiber; Miaad Bader, Tatiana Lenchinski, Inbar Meningher, Vardit Rubovitch, Yiffat Katz, Etia Cohen, Yankel Gabet, Michal Rotenberg, Ehud (Udi) Wolf, Chaim G. Pick
      Abstract: Synthetic cannabinoids are psychoactive substances designed to mimic the euphorigenic effects of the natural cannabis. Novel unregulated compounds appear once older compounds become illegal. It has been previously reported that synthetic cannabinoids are different than Δ9-tetrahydrocannabinol (Δ9-THC) as they have chemical structures unrelated to Δ9-THC, different metabolism and, often, greater toxicity. This study aimed to investigate the effects of three novel synthetic cannabinoids and pure Δ9-THC on body temperature, nociceptive threshold, anxiety, memory function, locomotor and exploratory parameters, and depression. We performed a battery of behavioural and motor tests starting 50 minutes post i.p. injection of each drug to adult ICR mice. The synthetic cannabinoids that were used are AB-FUBINACA, AB-CHMINACA and PB-22. All synthetic cannabinoids and Δ9-THC caused hypothermia, but only Δ9-THC induced a clear antinociceptive effect. All synthetic cannabinoids and Δ9-THC caused decreased anxiety levels, spatial memory deficits and decreased exploratory behaviour as measured in the elevated plus maze, Y-maze and staircase paradigm, respectively. However, all synthetic cannabinoids but not Δ9-THC demonstrated decreased locomotor activity in the staircase test. Moreover, only AB-FUBINACA and Δ9-THC affected the gait balance and grip strength of the mice as was assessed by the latency time to fall from a rod. In the forced swimming test, PB-22 caused elevated depression-like behaviour while AB-FUBINACA induced a reversed effect. These results suggest varied effects among different synthetic cannabinoids and Δ9-THC. Further studies are needed to characterize the overall effects and differences between these synthetic cannabinoids and Δ9-THC.Varied effects were found among different synthetic cannabinoids (AB-CHMINACA, AB-FUBINACA and PB-22) and Δ9-THC in mice. All synthetic cannabinoids and Δ9-THC caused hypothermia, but only Δ9-THC induced a clear antinociceptive effect. All synthetic cannabinoids and Δ9-THC caused decreased anxiety levels, spatial memory deficits and decreased exploratory behaviour. However, all synthetic cannabinoids but not Δ9-THC demonstrated decreased locomotor activity in the staircase test.
      PubDate: 2018-02-08T23:05:41.564969-05:
      DOI: 10.1111/adb.12606
  • Activation of amylin receptors attenuates alcohol-mediated behaviours in
    • Authors: Aimilia Lydia Kalafateli; Daniel Vallöf, Elisabet Jerlhag
      Abstract: Alcohol expresses its reinforcing properties by activating areas of the mesolimbic dopamine system, which consists of dopaminergic neurons projecting from the ventral tegmental area to the nucleus accumbens. The findings that reward induced by food and addictive drugs involve common mechanisms raise the possibility that gut–brain hormones, which control appetite, such as amylin, could be involved in reward regulation. Amylin decreases food intake, and despite its implication in the regulation of natural rewards, tenuous evidence support amylinergic mediation of artificial rewards, such as alcohol. Therefore, the present experiments were designed to investigate the effect of salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, on various alcohol-related behaviours in rodents. We showed that acute sCT administration attenuated the established effects of alcohol on the mesolimbic dopamine system, particularly alcohol-induced locomotor stimulation and accumbal dopamine release. Using the conditioned place preference model, we demonstrated that repeated sCT administration prevented the expression of alcohol's rewarding properties and that acute sCT administration blocked the reward-dependent memory consolidation. In addition, sCT pre-treatment attenuated alcohol intake in low alcohol-consuming rats, with a more evident decrease in high alcohol consumers in the intermittent alcohol access model. Lastly, sCT did not alter peanut butter intake, blood alcohol concentration and plasma corticosterone levels in mice. Taken together, the present data support that amylin signalling is involved in the expression of alcohol reinforcement and that amylin receptor agonists could be considered for the treatment of alcohol use disorder in humans.We show that acute sCT administration attenuates the effects of alcohol on the mesolimbic dopamine system, particularly alcohol-induced locomotor stimulation and accumbal dopamine release. Using the conditioned place preference model, we demonstrate that repeated sCT administration prevents the expression of alcohol's rewarding properties and that acute sCT administration blocks the reward-dependent memory consolidation. In addition, sCT pre-treatment attenuates alcohol intake in low alcohol-consuming rats, with a more evident decrease in high alcohol consumers in the intermittent alcohol access model.
      PubDate: 2018-02-06T00:50:41.766435-05:
      DOI: 10.1111/adb.12603
  • Acupuncture inhibition of methamphetamine-induced behaviors, dopamine
           release and hyperthermia in the nucleus accumbens: mediation of group II
    • Authors: Nam Jun Kim; Yeonhee Ryu, Bong Hyo Lee, Suchan Chang, Yu Fan, Young S. Gwak, Chae Ha Yang, Kyle B. Bills, Scott C. Steffensen, Jin Suk Koo, Eun Young Jang, Hee Young Kim
      Abstract: Methamphetamine (METH) increases metabolic neuronal activity in the mesolimbic dopamine (DA) system and mediates the reinforcing effect. To explore the underlying mechanism of acupuncture intervention in reducing METH-induced behaviors, we investigated the effect of acupuncture on locomotor activity, ultrasonic vocalizations, extracellular DA release in the nucleus accumbens (NAcs) using fast-scan cyclic voltammetry and alterations of brain temperature (an indicator of local brain metabolic activity) produced by METH administration. When acupuncture was applied to HT7, but not TE4, both locomotor activity and 50-kHz ultrasonic vocalizations were suppressed in METH-treated rats. Acupuncture at HT7 attenuated the enhancement of electrically stimulated DA release in the NAc of METH-treated rats. Systemic injection of METH produced a sustained increase in NAc temperature, which was reversed by the DA D1 receptor antagonist SCH 23390 or acupuncture at HT7. Acupuncture inhibition of METH-induced NAc temperature was prevented by pre-treatment with a group II metabotropic glutamate receptors (mGluR2/3) antagonist EGLU into the NAc or mimicked by injection of an mGluR2/3 agonist DCG-IV into the NAc. These results suggest that acupuncture reduces extracellular DA release and metabolic neuronal activity in the NAc through activation of mGluR2/3 and suppresses METH-induced affective states and locomotor behavior.The effect of acupuncture on methamphetamine-induced behaviors and the underlying mechanisms are unclear.The present study examined the effect of acupuncture on locomotor activity, ultrasonic vocalization, dopamine release and brain temperature in acute methamphetamine-treated rats and possible mediation of mGluR2/3.Our findings suggest that acupuncture reduces extracellular DA release and metabolic neuronal activity in the NAc through activation of mGluR2/3 and suppresses methamphetamine-induced affective states and locomotor behavior.
      PubDate: 2018-01-23T23:36:13.133839-05:
      DOI: 10.1111/adb.12587
  • Cocaine conditioned place preference: unexpected suppression of preference
           due to testing combined with strong conditioning
    • Authors: Lucile Marion-Poll; Antoine Besnard, Sophie Longueville, Emmanuel Valjent, Olivia Engmann, Jocelyne Caboche, Denis Hervé, Jean-Antoine Girault
      Abstract: Conditioned place preference (CPP) is widely used for evaluating the rewarding effects of drugs. Like other memories, CPP is proposed to undergo reconsolidation during which it is unstable and sensitive to pharmacological inhibition. Previous studies have shown that cocaine CPP can be apparently erased by extracellular signal-regulated kinase (ERK) pathway inhibition during cocaine reconditioning (re-exposure to the drug-paired environment in the presence of the drug). Here, we show that blockade of D1 receptors during reconditioning prevented ERK activation and induced a loss of CPP. However, we also unexpectedly observed a CPP disappearance in mice that underwent testing and reconditioning with cocaine alone, specifically in strong conditioning conditions. The loss was due to the intermediate test. CPP was not recovered with reconditioning or priming in the short term, but it spontaneously reappeared after a month. When we challenged the D1 antagonist-mediated erasure, we observed that both a high dose of cocaine and a first CPP test were required for this effect. Our results also suggest a balance between D1-dependent ERK pathway activation and an A2a-dependent mechanism in D2 striatal neurons in controlling CPP expression. Our data reveal that, paradoxically, a simple CPP test can induce a complete (but transient) loss of place preference following strong but not weak cocaine conditioning. This study emphasizes the complex nature of CPP memory and the importance of multiple parameters that must be taken into consideration when investigating reconsolidation.Blockade of D1 receptors during reconditioning prevented extracellular signal-regulated kinase activation and induced a loss of conditioned place preference (CPP). We also unexpectedly observed a CPP disappearance in mice that underwent testing and reconditioning with cocaine alone, specifically in strong conditioning conditions. Our data emphasize the complex nature of CPP memory and the importance of multiple parameters that must be taken into consideration when investigating reconsolidation.
      PubDate: 2018-01-10T00:30:45.467599-05:
      DOI: 10.1111/adb.12600
  • Time-course and dynamics of obesity-related behavioral changes induced by
           energy-dense foods in mice
    • Authors: Jose Espinosa-Carrasco; Aurelijus Burokas, Marta Fructuoso, Ionas Erb, Elena Martín-García, Miriam Gutiérrez-Martos, Cedric Notredame, Rafael Maldonado, Mara Dierssen
      Abstract: Obesity represents an important risk factor contributing to the global burden of disease. The current obesogenic environment with easy access to calorie-dense foods is fueling this obesity epidemic. However, how these foods contribute to the progression of feeding behavior changes that lead to overeating is not well understood and needs systematic assessment. Using novel automated methods for the high-throughput screening of behavior, we here examine mice meal pattern upon long-term exposure to a free-choice chocolate-mixture diet and a high-fat diet with face validity for a rapid development of obesity induced by unhealthy food regularly consumed in our societies. We identified rapid diet-specific behavioral changes after exposure to those high-caloric diets. Mice fed with high-fat chow, showed long-lasting meal pattern disturbances, which initiate with a stable loss of circadian feeding rhythmicity. Mice receiving a chocolate-mixture showed qualitatively similar changes, though less marked, consisting in a transient disruption of the feeding behavior and the circadian feeding rhytmicity. Strikingly, compulsive-like eating behavior is triggered immediately after exposure to both high-fat food and chocolate-mixture diet, well before any changes in body weight could be observed. We propose these changes as behavioral biomarkers of prodromal states of obesity that could allow early intervention.Using a high-throughput recording system, we analyzed the changes in feeding behavior in mice fed with two types of craved palatable foods: a high-fat and a chocolate-based diet. Upon introduction of the high-fat diet, mice showed long-lasting alterations in meal pattern, such as the loss of circadian feeding rhythmicity, inflexibility and compulsive-like food. Chocolate-based diet induced only a transient but similar alteration of feeding behavior. Our results suggest that early behavioral changes might be used as biomarkers of obesity prodromal states.
      PubDate: 2018-01-10T00:17:00.735208-05:
      DOI: 10.1111/adb.12595
  • Beyond genome-wide significance: integrative approaches to the
           interpretation and extension of GWAS findings for alcohol use disorder
    • Authors: Jessica E. Salvatore; Shizhong Han, Sean P. Farris, Kristin M. Mignogna, Michael F. Miles, Arpana Agrawal
      Abstract: Alcohol use disorder (AUD) is a heritable complex behavior. Due to the highly polygenic nature of AUD, identifying genetic variants that comprise this heritable variation has proved to be challenging. With the exception of functional variants in alcohol metabolizing genes (e.g. ADH1B and ALDH2), few other candidate loci have been confidently linked to AUD. Genome-wide association studies (GWAS) of AUD and other alcohol-related phenotypes have either produced few hits with genome-wide significance or have failed to replicate on further study. These issues reinforce the complex nature of the genetic underpinnings for AUD and suggest that both GWAS studies with larger samples and additional analysis approaches that better harness the nominally significant loci in existing GWAS are needed. Here, we review approaches of interest in the post-GWAS era, including in silico functional analyses; functional partitioning of single nucleotide polymorphism heritability; aggregation of signal into genes and gene networks; and validation of identified loci, genes and gene networks in postmortem brain tissue and across species. These integrative approaches hold promise to illuminate our understanding of the biological basis of AUD; however, we recognize that the main challenge continues to be the extremely polygenic nature of AUD, which necessitates large samples to identify multiple loci associated with AUD liability.Alcohol use disorder is heritable and highly polygenic. Genome-wide association studies (GWAS) of alcohol use disorder have produced few replicable genome-wide significant hits. In this paper, we review integrative approaches for harnessing the nominally significant genetic variation within existing alcohol use disorder genome-wide association studies. These approaches include single locus annotation, genome-wide aggregation and post-mortem and cross-species validation.
      PubDate: 2018-01-09T00:25:36.336497-05:
      DOI: 10.1111/adb.12591
  • Validation of a behavioral economic purchase task for assessing drug abuse
    • Authors: James MacKillop; Nicholas I. Goldenson, Matthew G. Kirkpatrick, Adam M. Leventhal
      Abstract: Behavioral economic purchase tasks quantify drug demand (i.e. reinforcing value of a drug) and have been used extensively to assess the value of various drugs among current users. However, purchase tasks have been rarely used with unfamiliar drugs to address a compound's abuse liability, and the current study sought to validate the paradigm in this capacity. Using a double-blind placebo-controlled within-subjects drug challenge design, the study evaluated differential drug demand on an experimental drug purchase task for a 20 mg dose of oral D-amphetamine (versus placebo), a prototypic psychostimulant, in 98 stimulant-naïve participants. Compared with placebo, amphetamine significantly increased intensity, breakpoint and Omax, and significantly decreased elasticity. Mechanistic analyses revealed that Omax and breakpoint mediated the relationship between subjective drug effects and ‘willingness to take again’, a putative indicator of liability via motivation for future drug-seeking behavior. These findings validate the purchase task paradigm for quantifying the reinforcing value and, in turn, abuse liability of unfamiliar compounds, providing a foundation for a variety of future applications.Purchase tasks are often used for measuring drug reinforcing value, but have not been used to screen unfamiliar compounds to inform abuse liability. Comparing a prototypic psychostimulant (D-amphetamine) to placebo in drug naïve participants, this study found greater reinforcing value on an experimental drug purchase task and that the task indices linked subjective effects and motivation for future consumption. These findings support the use of purchase tasks for measuring a compound's addiction potential in healthy volunteers.
      PubDate: 2018-01-05T04:37:18.747491-05:
      DOI: 10.1111/adb.12592
  • Chemogenetic inhibition of direct pathway striatal neurons normalizes
           pathological, cue-induced reinstatement of drug-seeking in rats
    • Authors: Lindsay M. Yager; Aaron F. Garcia, Elizabeth A. Donckels, Susan M. Ferguson
      Abstract: Addiction to drugs such as cocaine is marked by cycles of compulsive drug-taking and drug-seeking behavior. Although the transition to addiction is thought to recruit neural processes in dorsal striatum, little is known regarding the role of dorsal striatal projections to the substantia nigra (i.e. the direct pathway) in regulating these behaviors. Combining a Cre-recombinase-dependent chemogenetic approach with a cocaine self-administration paradigm that produces both low-risk and high-risk addiction phenotypes, we examined the effect of transiently decreasing direct pathway activity in the dorsomedial striatum on drug-taking and drug-seeking under conditions of normal and pathological drug use. Surprisingly, transient inhibition of direct pathway striatal neurons had no effect on several measures of addictive behavior during ongoing drug use, including loss of control over drug intake, high motivation to obtain drug and drug use despite negative consequences (i.e. drug use paired with foot shock). However, chemogenetic inhibition of these neurons during reinstatement reduced cue-induced drug-seeking, but only in the high-risk addiction phenotype group. Cue-induced reinstatement was relatively normal in the low-risk addiction phenotype group, as well as following reinstatement to cues associated with sucrose pellet consumption. These results demonstrate that dorsomedial direct pathway striatal neurons play a very specific role in addictive behaviors, which is to regulate the pathological drug-seeking that accompanies relapse.Although drug addiction continues to pose a major public health crisis, treatment options remain limited, in part due to our incomplete understanding of the cells and circuits that regulate recreational drug use as well as those that underlie drug addiction and relapse. The present set of experiments sought to address the role of striatal cells that project to the substantia nigra (i.e. the direct/‘go’ pathway) in casual and pathological drug use. The findings from this work reveal a novel and specific contribution of direct pathway cells in addiction, which is to regulate drug-seeking following compulsive drug use.
      PubDate: 2018-01-05T04:25:42.256735-05:
      DOI: 10.1111/adb.12594
  • Appetitive to aversive counter-conditioning as intervention to reduce
           reinstatement of reward-seeking behavior: the role of the serotonin
    • Authors: Peter Karel; Amanda Almacellas-Barbanoj, Jeffrey Prijn, Anne-Marije Kaag, Liesbeth Reneman, Michel M.M. Verheij, Judith R. Homberg
      Abstract: Counter-conditioning can be a valid strategy to reduce reinstatement of reward-seeking behavior. However, this has not been tested in laboratory animals with extended cocaine-taking backgrounds nor is it well understood, which individual differences may contribute to its effects. Here, we set out to investigate the influence of serotonin transporter (5-HTT) genotype on the effectiveness of counter-conditioning after extended access to cocaine self-administration. To this end, 5-HTT+/+ and 5-HTT−/− rats underwent a touch screen-based approach to test if reward-induced reinstatement of responding to a previously counter-conditioned cue is reduced, compared with a non-counter-conditioned cue, in a within-subject manner. We observed an overall extinction deficit of cocaine-seeking behavior in 5-HTT−/− rats and a resistance to punishment during the counter-conditioning session. Furthermore, we observed a significant decrease in reinstatement to cocaine and sucrose associated cues after counter-conditioning but only in 5-HTT+/+ rats. In short, we conclude that the paradigm we used was able to produce effects of counter-conditioning of sucrose seeking behavior in line with what is described in literature, and we demonstrate that it can be effective even after long-term exposure to cocaine, in a genotype-dependent manner.Typical extinction training is insufficient to prevent reinstatement of drug seeking in laboratory animals. Here, we describe a touch screen-based counter-conditioning procedure that is designed to reduce reward induced reinstatement in wild-type (5-HTT+/+) and serotonin transporter knockout rats (5-HTT−/−) after extended access to cocaine or sucrose self-administration. Our results suggest that the procedure was able to reduce reward induced reinstatement in 5-HTT+/+ but not in 5-HTT−/− rats.
      PubDate: 2018-01-02T00:40:38.961885-05:
      DOI: 10.1111/adb.12596
  • Acute and chronic modulation of striatal endocannabinoid-mediated
           plasticity by nicotine
    • Authors: Louise Adermark; Julia Morud, Amir Lotfi, Mia Ericson, Bo Söderpalm
      Abstract: The endocannabinoid (eCB) system modulates several phenomena related to addictive behaviors, and drug-induced changes in eCB signaling have been postulated to be important mediators of physiological and pathological reward-related synaptic plasticity. Here, we studied eCB-mediated long-term depression (eCB-LTD) in the dorsolateral striatum, a brain region critical for acquisition of habitual and automatic behavior. We report that nicotine differentially affects ex vivo eCB signaling depending on previous exposure in vivo. In the nicotine-naïve brain, nicotine facilitates eCB-signaling and LTD, whereas tolerance develops to this facilitating effect after subchronic exposure in vivo. In the end, a progressive impairment of eCB-induced LTD is established after protracted withdrawal from nicotine. Endocannabinoid-LTD is reinstated 6 months after the last drug injection, but a brief period of nicotine re-exposure is sufficient to yet again impair eCB-signaling. LTD induced by the cannabinoid 1 receptor agonist WIN55,212-2 is not affected, suggesting that nicotine modulates eCB production or release. Nicotine-induced facilitation of eCB-LTD is occluded by the dopamine D2 receptor agonist quinpirole, and by the muscarinic acetylcholine receptor antagonist scopolamine. In addition, the same compounds restore eCB-LTD during protracted withdrawal. Nicotine may thus modulate eCB-signaling by affecting dopaminergic and cholinergic neurotransmission in a long-lasting manner. Overall, the data presented here suggest that nicotine facilitates eCB-LTD in the initial phase, which putatively could promote neurophysiological and behavioral adaptations to the drug. Protracted withdrawal, however, impairs eCB-LTD, which may influence or affect the ability to maintain cessation.Acute nicotine exposure facilitates striatal eCB signaling, which might promote habit formation and addiction. In contrast, repeated administration to nicotine in vivo, followed by protracted abstinence, results in impaired eCB signaling for several months, which might affect behavioral flexibility and putatively the recovery from addiction. Dopamine D2 receptors play a key role in mediating both these effects.
      PubDate: 2018-01-02T00:30:40.484728-05:
      DOI: 10.1111/adb.12598
  • Issue Information
    • Pages: 529 - 530
      Abstract: No abstract is available for this article.
      PubDate: 2018-02-14T03:53:30.154922-05:
      DOI: 10.1111/adb.12562
  • Methamphetamine binge administration dose-dependently enhanced negative
           affect and voluntary drug consumption in rats following prolonged
           withdrawal: role of hippocampal FADD
    • Authors: Rubén García-Cabrerizo; M. Julia García-Fuster
      Abstract: While prior studies have established various interacting mechanisms and neural consequences (i.e. monoaminergic nerve terminal damage) that might contribute to the adverse effects caused by methamphetamine administration, the precise mechanisms that mediate relapse during withdrawal remain unknown. This study evaluated the long-term consequences of binge methamphetamine administration (three pulses/day, every 3 hours, 4 days, i.p.; dose–response: 2.5, 5 and 7.5 mg/kg) in adult Sprague–Dawley rats at two behavioral levels following 25 days of withdrawal: (1) negative affect (behavioral despair—forced-swim test, and anhedonia—1% sucrose consumption, two-bottle choice test) and (2) voluntary methamphetamine consumption (20 mg/l, two-bottle choice test). Striatal and hippocampal brain samples were dissected to quantify monoamines content by high-performance liquid chromatography and to evaluate neurotoxicity (dopaminergic and serotonergic markers) and neuroplasticity markers [i.e. cell fate regulator (Fas-associated protein with death domain) FADD] by Western blot. The results showed that methamphetamine administration induced dose-dependent negative effects during prolonged withdrawal in adult rats. In particular, rats treated repeatedly with methamphetamine (7.5 mg/kg) showed (1) enhanced negative affect—increased anhedonia associated with behavioral despair, (2) increased voluntary methamphetamine consumption, (3) enhanced neurotoxicity—decreased dopamine and metabolites in striatum and decreased serotonin in hippocampus, (4) altered neuroplasticity markers—decreased FADD protein and increased p-FADD/FADD balance selectively in hippocampus and (5) higher consumption rates of methamphetamine that were associated with lower FADD content in hippocampus. These results confirm that methamphetamine withdrawal dose-dependently induced negative affect and decreased monoamines content, while also increased voluntary methamphetamine consumption and suggested a role for hippocampal FADD neuroplasticity in these drug-withdrawal adaptations.Methamphetamine administration induced dose-dependent negative effects during prolonged withdrawal in adult rats. Mainly, rats treated repeatedly with methamphetamine (7.5 mg/kg) showed: (1) enhanced negative affect—increased anhedonia associated with behavioral despair, (2) increased voluntary methamphetamine consumption, (3) enhanced neurotoxicity—decreased brain dopamine and serotonin, (4) altered neuroplasticity—decreased hippocampal FADD protein, and (5) higher consumption rates of methamphetamine were associated with lower hippocampal FADD content. Thus, these results suggested a role for hippocampal FADD neuroplasticity in these drug-withdrawal adaptations.
      PubDate: 2017-12-28T04:00:37.240837-05:
      DOI: 10.1111/adb.12593
  • Extinction and reinstatement of an operant responding maintained by food
           in different models of obesity
    • Authors: Aurelijus Burokas; Elena Martín-García, Jose Espinosa-Carrasco, Ionas Erb, Jerome McDonald, Cedric Notredame, Mara Dierssen, Rafael Maldonado
      Abstract: A major problem in treating obesity is the high rate of relapse to abnormal food-taking habits after maintaining an energy balanced diet. Alterations of eating behavior such as compulsive-like behavior and lack of self-control over food intake play a critical role in relapse. In this study, we used an operant paradigm of food-seeking behavior on two different diet-induced obesity models, a free-choice chocolate-mixture diet and a high-fat diet with face validity for a rapid development of obesity or for unhealthy food regularly consumed in our societies. A reduced operant performance and motivation for the hedonic value of palatable chocolate pellets was revealed in both obesity mouse models. However, only mice exposed to high-fat diet showed an increased compulsive-like behavior in the absence of the reinforcer further characterized by impaired operant learning, enhanced impulsivity and intensified inflexibility. We used principal component analysis to globally identify the specific behaviors responsible for the differences among diet groups. Learning impairment and inflexible behaviors contributed to a first principal component, explaining the largest proportion of the variance in the high-fat diet mice phenotype. Reinforcement, impulsion and compulsion were the main contributors to the second principal component explaining the differences in the chocolate-mixture mice behavioral phenotype. These behaviors were not exclusive of chocolate group because some high-fat individuals showed similar values on this component. These data indicate that extended access to hypercaloric diets differentially modifies operant behavior learning, behavioral flexibility, impulsive-like and compulsive-like behavior, and these effects were dependent on the exposure to each specific diet.We have used prolonged exposure to a free-choice of chocolate-mixture diet and to a forced exposition to high-fat food in mice to investigate the consequences of long-term obesogenic diet exposure in reinstatement of food-seeking behavior. Principal component analysis (PCA) identified that the major source of variability was related to learning impairment/inflexibility (PC1), setting the high-fat group apart from both lean controls and the obese chocolate-mixture group and also explaining a considerable amount of the variation among obese high-fat individuals.
      PubDate: 2017-12-28T03:25:39.286744-05:
      DOI: 10.1111/adb.12597
  • Rich club and reward network connectivity as endophenotypes for alcohol
           dependence: a diffusion tensor imaging study
    • Authors: Nabi Zorlu; Necip Çapraz, Esra Oztekin, Başak Bagci, Maria A. Di Biase, Andrew Zalesky, Fazıl Gelal, Emre Bora, Ercan Durmaz, Lütfullah Beşiroğlu, Aybala Sarıçiçek
      Abstract: We aimed to examine the whole-brain white matter connectivity and local topology of reward system nodes in patients with alcohol use disorder (AUD) and unaffected siblings, relative to healthy comparison individuals. Diffusion-weighted magnetic resonance imaging scans were acquired from 18 patients with AUD, 15 unaffected siblings of AUD patients and 15 healthy controls. Structural networks were examined using network-based statistic and connectomic analysis. Connectomic analysis showed a significant ordered difference in normalized rich club organization (AUD  AUD) for both nodal clustering coefficient and nodal local efficiency in reward system nodes, particularly left caudate, right putamen and left hippocampus. Network-based statistic analyses showed that AUD group had significantly weaker connectivity than controls in the right hemisphere, mostly in the edges connecting putamen and hippocampus with other brain regions. Our results suggest that reward system network abnormalities, especially in subcortical structures, and impairments in rich-club organization might be related to the familial predisposition for AUD.We aimed to examine the whole-brain white matter connectivity and local topology of reward system nodes in patients with alcohol use disorder (AUD) and unaffected siblings, relative to healthy comparison individuals. We found rank ordered differences (Control > Sibling > AUD) for both nodal clustering coefficient and nodal local efficiency in the left caudate, right putamen, and left hippocampus. Our results suggest that reward system network abnormalities might be related to the familial predisposition for AUD.
      PubDate: 2017-12-27T04:29:15.887536-05:
      DOI: 10.1111/adb.12599
  • Sex hormones in alcohol consumption: a systematic review of evidence
    • Authors: Almila Erol; Ada M.-C. Ho, Stacey J. Winham, Victor M. Karpyak
      Abstract: Sex hormones play an important role in establishing sex-distinctive brain structural and functional variations that could contribute to the sex differences in alcohol consumption behavior. Here, we systematically reviewed articles that studied sex hormone impacts on alcohol consumption and alcohol use disorder (AUD). An extensive literature search conducted in MEDLINE, PubMed, Scopus and CINAHL databases identified 776 articles, which were then evaluated for pre-specified criteria for relevance and quality assurance. A total of 50 articles, including 19 human studies and 31 animal studies, were selected for this review. Existing evidence supports the association of increased testosterone level and increased risk for alcohol use and AUD in males but results are inconclusive in females. In contrast, the evidence supports the association of increased estrogen level and increased alcohol use in females, with mixed findings reported in males. Much less is known about the impact of progestins on alcohol use and misuse in human subjects. Future observational and experimental studies conducted in both sexes with a comprehensive hormone panel are needed to elucidate the impact of the interplay between various sex hormone levels during various developmental stages on alcohol use-related phenotypes and AUD.Sex hormones play an important role in establishing the sex differences in alcohol consumption behavior. Here, we systematically reviewed articles that studied sex hormone impacts on alcohol consumption and alcohol use disorder. Among the 50 articles that fulfilled selection requirements, 19 were human studies and 31 were animal studies. Existing evidence supports associations between sex hormones and alcohol use, but such associations were different between sexes and among developmental stages. Future studies with improved methodologies may elucidate these associations.
      PubDate: 2017-12-27T04:15:41.398584-05:
      DOI: 10.1111/adb.12589
  • Rat brain CYP2D activity alters in vivo central oxycodone metabolism,
           levels and resulting analgesia
    • Authors: Douglas M. McMillan; Sharon Miksys, Rachel F. Tyndale
      Abstract: Oxycodone is metabolized by CYP2D to oxymorphone. Despite oxymorphone being a more potent opioid-receptor agonist, its contribution to oxycodone analgesia may be minor because of low peripheral production, low blood–brain barrier permeability and central nervous system efflux. CYP2D metabolism within the brain may contribute to variation in central oxycodone and oxymorphone levels, thereby affecting analgesia. Brain CYP2D expression and activity are subject to exogenous regulation; nicotine induces rat brain, but not liver, CYP2D consistent with higher brain CYP2D in smokers. We assessed the role of rat brain CYP2D in orally administered oxycodone metabolism (in vivo brain microdialysis) and analgesia (tail-flick test) by inhibiting brain CYP2D selectively with intracerebroventricular propranolol (mechanism-based inhibitor) and inducing brain CYP2D with nicotine. Inhibiting brain CYP2D increased brain oxycodone levels (1.8-fold; P 
      PubDate: 2017-12-21T00:12:13.691694-05:
      DOI: 10.1111/adb.12590
  • Neurological, nutritional and alcohol consumption factors underlie
           cognitive and motor deficits in chronic alcoholism
    • Authors: Rosemary Fama; Anne-Pascale Le Berre, Cheshire Hardcastle, Stephanie A. Sassoon, Adolf Pfefferbaum, Edith V. Sullivan, Natalie M. Zahr
      Abstract: Variations in pattern and extent of cognitive and motor impairment occur in alcoholism (ALC). Causes of such heterogeneity are elusive and inconsistently accounted for by demographic or alcohol consumption differences. We examined neurological and nutritional factors as possible contributors to heterogeneity in impairment. Participants with ALC (n = 96) and a normal comparison group (n = 41) were examined on six cognitive and motor domains. Signs of historically determined subclinical Wernicke's encephalopathy were detected using the Caine et al. criteria, which were based on postmortem examination and chart review of antemortem data of alcoholic cases with postmortem evidence for Wernicke's encephalopathy. Herein, four Caine criteria provided quantification of dietary deficiency, cerebellar dysfunction, low general cognitive functioning and oculomotor abnormalities in 86 of the 96 ALC participants. Subgroups based on Caine criteria yielded a graded effect, where those meeting more criteria exhibited greater impairment than those meeting no to fewer criteria. These results could not be accounted for by history of drug dependence. Multiple regression indicated that compromised performance on ataxia, indicative of cerebellar dysfunction, predicted non-mnemonic and upper motor deficits, whereas low whole blood thiamine level, consistent with limbic circuit dysfunction, predicted mnemonic deficits. This double dissociation indicates biological markers that contribute to heterogeneity in expression of functional impairment in ALC. That non-mnemonic and mnemonic deficits are subserved by the dissociable neural systems of frontocerebellar and limbic circuitry, both commonly disrupted in ALC, suggests neural mechanisms that can differentially affect selective functions, thereby contributing to heterogeneity in pattern and extent of dysfunction in ALC.Dissociable alcohol, nutritional and neurological factors were predictive of selective cognitive and motor deficits in sober alcoholics. The study revealed a double dissociation: lower thiamine level and greater lifetime alcohol consumption selectively predicted episodic memory deficits, whereas ataxia selectively predicted executive function and upper motor deficits. This double dissociation identified biological markers that contribute to the heterogeneity in expression of functional impairment in alcoholism and highlights the importance of assessing occult Wernicke's encephalitis in individuals with alcohol use disorder.
      PubDate: 2017-12-15T04:22:12.564547-05:
      DOI: 10.1111/adb.12584
  • Quantitative evaluation of cue-induced reinstatement model for
           evidence-based experimental optimization
    • Authors: Julia Oberhofer; Hamid R. Noori
      Abstract: Cue-induced reinstatement is a widely used model for investigating relapse of reward-seeking behavior with high face validity in relation to clinical observations. Yet, face validity is not sufficient to evaluate an animal model, and quantitative, evidence-based analysis is required to estimate the ultimate applicability of this paradigm. Furthermore, such analysis would allow an accurate and reproducible design of future experiments. Here, we conducted meta-analysis and cluster analysis to characterize the impact of cue type (visual, auditory, olfactory or combinations thereof), intensity (e.g. light frequency, sound volume and odor concentration), reward type (e.g. different drugs of abuse, sucrose and food pellets) and model parameters (e.g. housing condition, age, gender and strain of animals) on reinstatement levels. We selected 184 publications for meta-analysis based on inclusion criteria with a total number of 3889 rats. Our analysis suggested that the exact level of reinstatement depends on neither cue type, nor intensity nor on the type of reward. While all cues induced reinstatement to reward-seeking behavior, it is the model parameters, in particular, the housing conditions, age and strain, that defined the final reinstatement levels. In particular, single-housed, adolescent, Wistar or Lister Hooded rats showed significantly higher reinstatement than adult, Sparague-Dawley rats housed in groups. Our findings suggest that model parameters (for example, single housing) evoke stress-induced behaviors that affect reinstatement more than cue/reward factors.Cue-induced reinstatement is a widely used paradigm to investigate relapse to reward-seeking behavior with high face validity to clinical observations. However, due to large discrepancies in the design of such experiments, it is hard to evaluate its general validity. Our analysis suggests that exact levels of reinstatement neither depends on the cue type or intensity nor on the choice of reward. All cues induce reinstatement to reward-seeking behavior, but model parameters particularly housing conditions, age, and strain are critical.
      PubDate: 2017-12-14T00:35:56.960184-05:
      DOI: 10.1111/adb.12588
  • Activation of glucagon-like peptide-1 receptors in the nucleus accumbens
           attenuates cocaine seeking in rats
    • Authors: Nicole S. Hernandez; Bernadette O'Donovan, Pavel I. Ortinski, Heath D. Schmidt
      Abstract: Recent evidence indicates that activation of glucagon-like peptide-1 (GLP-1) receptors reduces cocaine-mediated behaviors and cocaine-evoked dopamine release in the nucleus accumbens (NAc). However, no studies have examined the role of NAc GLP-1 receptors in the reinstatement of cocaine-seeking behavior, an animal model of relapse. Here, we show that systemic infusion of a behaviorally relevant dose of the GLP-1 receptor agonist exendin-4 penetrated the brain and localized with neurons and astrocytes in the NAc. Administration of exendin-4 directly into the NAc core and shell subregions significantly attenuated cocaine priming-induced reinstatement of drug-seeking behavior. These effects were not due to deficits in operant responding or suppression of locomotor activity as intra-accumbal exendin-4 administration had no effect on sucrose-seeking behavior. To determine the effects of GLP-1 receptor activation on neuronal excitability, exendin-4 was bath applied to ex vivo NAc slices from cocaine-experienced and saline-experienced rats following extinction of cocaine-taking behavior. Exendin-4 increased the frequency of action potential firing of NAc core and shell medium spiny neurons in cocaine-experienced rats while no effect was observed in saline controls. In contrast, exendin-4 did not affect the frequency or amplitude of spontaneous excitatory postsynaptic currents or alter the paired-pulse ratios of evoked excitatory postsynaptic currents. These effects were not associated with altered expression of GLP-1 receptors in the NAc following cocaine self-administration. Taken together, these findings indicate that increased activation of GLP-1 receptors in the NAc during cocaine abstinence increases intrinsic, but not synaptic, excitability of medium spiny neurons and is sufficient to reduce cocaine-seeking behavior.Emerging evidence indicates that glucagon-like peptide-1 (GLP-1) signaling plays an important role in cocaine-mediated behaviors. Here, we show that a GLP-1 receptor agonist administered systemically penetrates the brain, localizes in the nucleus accumbens and attenuates the reinstatement of cocaine-seeking behavior, an animal model of relapse. These behavioral effects were associated with increased action potential firing in accumbens medium spiny neurons.
      PubDate: 2017-12-11T00:58:15.626033-05:
      DOI: 10.1111/adb.12583
  • Central administration of galanin N-terminal fragment 1–15 decreases the
           voluntary alcohol intake in rats
    • Authors: Carmelo Millón; Antonio Flores-Burgess, Estela Castilla-Ortega, Belén Gago, María García-Fernandez, Antonia Serrano, Fernando Rodriguez de Fonseca, José Angel Narváez, Kjell Fuxe, Luis Santín, Zaida Díaz-Cabiale
      Abstract: Alcohol consumption is considered a major risk factor for disease and mortality worldwide. In the absence of effective treatments in alcohol use disorders, it is important to find new biological targets that could modulate alcohol consumption. We tested the role of the N-terminal galanin fragment (1–15) [GAL(1–15)] in voluntary ethanol consumption in rats using the two-bottle choice paradigm as well as compare the effects of GAL(1–15) with the whole molecule of GAL. We describe for the first time that GAL(1–15), via central mechanisms, induces a strong reduction in preference and ethanol consumption in rats. These effects were significantly different than GAL. GAL receptor (GALR) 2 was involved in these effects, because the specific GALR2 antagonist M871 blocked GAL(1–15) mediated actions in preference and ethanol intake. Importantly, the mechanism of this action involves changes in GALR expression and also in immediate-early gene C-Fos and receptors-internalization-related gene Rab5 in the striatum. The relevance of the striatum as a target for GAL(1–15) was supported by the effect of GAL(1–15) on the locomotor activity of rats after ethanol administration. These results may give the basis for the development of novel therapeutics strategies using GAL(1–15) analogues for the treatment of alcohol use disorders in humans.The N-terminal fragment GAL(1–15) induces a strong reduction in preference and ethanol consumption in rats. The mechanism of this action involves changes in striatum in GAL receptors expression and also in immediate-early gene C-Fos and receptors-internalization-related gene Rab5.
      PubDate: 2017-12-06T00:25:34.411163-05:
      DOI: 10.1111/adb.12582
  • Adolescent impulsivity as a sex-dependent and subtype-dependent predictor
           of impulsivity, alcohol drinking and dopamine D2 receptor expression in
           adult rats
    • Authors: Lindsey R. Hammerslag; Amogh P. Belagodu, Olubankole A. Aladesuyi Arogundade, Angela G. Karountzos, Qingrou Guo, Roberto Galvez, Brent W. Roberts, Joshua M. Gulley
      Abstract: Impulsivity is a personality trait associated with a heightened risk for drug use and other psychiatric conditions. Because impulsivity-related disorders typically emerge during adolescence, there has been interest in exploring methods for identifying adolescents that will be at risk to develop substance use disorders in adulthood. Here, we used a rodent model to assess inhibitory control (impulsive action) and impulsive decision making (impulsive choice) during adolescence (43–50 days old) or adulthood (93–100 days old) and then examined the impact of development on these impulsivity traits by re-testing rats 50 days later. Impulsive action was not stable from adolescence to adulthood in male rats and was lowest in adult male rats, relative to adolescents and female rats. Impulsive choice was stable across development and unaffected by age or sex. Next, we examined the connection between our model of impulsivity and two measures relevant to substance abuse research: the initiation of voluntary alcohol drinking and dopamine D2 receptor (D2R) expression in the prelimbic prefrontal cortex. Consumption of saccharin-sweetened ethanol during 30-minute sessions in adulthood was associated with adolescent, but not adult, impulsive action, particularly in male rats. Prelimbic D2R expression was reduced in individuals with high levels of impulsive choice, and this relationship appeared to be strongest among female rats. The results of this study demonstrate that impulsive choice, along with its connection to D2R expression, is relatively unchanged by the process of development. For impulsive action, however, individual levels of impulsivity during adolescence predict drinking in adulthood despite changes in the measure during development.Impulsive action changes unpredictably from adolescence to adulthood for male ratss, but is stable in female rats. Impulsive action, but not choice, predicts drinking in adulthood. Despite developmental changes in PFC, rats with high levels of impulsive choice (measured during adolescence or adulthood) have low levels of PFC dopamine D2 receptor expression later in adulthood.
      PubDate: 2017-12-05T22:11:26.623675-05:
      DOI: 10.1111/adb.12586
  • Neuropeptide CART prevents memory loss attributed to withdrawal of
           nicotine following chronic treatment in mice
    • Authors: Chandrashekhar D. Borkar; Sneha Sagarkar, Amul J. Sakharkar, Nishikant K. Subhedar, Dadasaheb M. Kokare
      Abstract: Although chronic nicotine administration does not affect memory, its withdrawal causes massive cognitive deficits. The underlying mechanisms, however, have not been understood. We test the role of cocaine- and amphetamine-regulated transcript peptide (CART), a neuropeptide known for its procognitive properties, in this process. The mice on chronic nicotine treatment/withdrawal were subjected to novel object recognition task. The capability of the animal to discriminate between the novel and familiar objects was tested and represented as discrimination index (DI); reduction in the index suggested amnesia. Nicotine for 49 days had no effect on DI, but 8-hour withdrawal caused a significant reduction, followed by full recovery at 24-hour withdrawal timepoint. Bilateral CART infusion in dorsal hippocampus rescued deficits in DI at 8-hours, whereas CART-antibody infusion into the dorsal hippocampus attenuated the recovery at 24-hours. Commensurate changes were observed in the CART as well as CART mRNA profiles in the hippocampus. CART mRNA expression and the peptide immunoreactivity did not change significantly following chronic nicotine treatment. However, there was a significant reduction at 8-hour withdrawal, followed by a drastic increase in CART immunoreactivity as well as CART mRNA at 24-hour withdrawal, compared with 8-hour withdrawal. Distinct α7-nicotinic receptor immunoreactivity was detected on the hippocampal CART neurons, suggesting cholinergic inputs. An increase in the synaptophysin immunoreactive elements around CART cells in the dentate gyrus, cornu ammonis 3 and subiculum at 24-hour post-withdrawal timepoint suggested neuronal plasticity. CART circuit dynamics in the hippocampus seems to modulate short-term memory associated with nicotine withdrawal.While chronic nicotine administration did not affect learning and memory, cognitive deficits in recognition memory were noted at 8-hour withdrawal. However, total recovery was recorded at 24-hour post-withdrawal timepoint. Concurrently, CART and synaptophysin expression was decreased at 8-hour, but reinstated at 24 hours following withdrawal. In addition, α7-nAch receptors were detected on CART neurons of CA3 and DG of hippocampus. We suggest that cholinergic inputs to the CART neurons may be an important component of the circuit encoding short-term memory.
      PubDate: 2017-11-29T05:36:51.82293-05:0
      DOI: 10.1111/adb.12579
  • Increased plasma oleoylethanolamide and palmitoleoylethanolamide levels
           correlate with inflammatory changes in alcohol binge drinkers: the case of
           HMGB1 in women
    • Authors: María Antón; Alicia Rodríguez-González, Inmaculada Concepción Rodríguez-Rojo, Antoni Pastor, Ángeles Correas, Antonia Serrano, Antonio Ballesta, Francisco Alén, Raquel Gómez de Heras, Rafael Torre, Fernando Rodríguez de Fonseca, Laura Orio
      Abstract: Alcohol binge drinking is a heavy pattern of alcohol consumption increasingly used by young people. In a previous study, we reported that young drinkers with a 2-year history of binge alcohol consumption had an overactivation of the innate immune system and peripheral inflammation when compared with controls. In the present study, we measured several biolipids that are fatty acid derivatives belonging to the acylethanolamide or 2-acylglycerol families in the plasma of the same subjects (n = 42; 20 men and 22 women). We found that during abstinence, alcohol binge drinkers had elevated plasma levels of oleoylethanolamide, palmitoleoylethanolamide, arachidonoylethanolamide, dihomo-γ-linolenoyl ethanolamide and linoleoyl ethanolamide, which positively correlated with changes in the mRNA expression of key inflammatory markers in peripheral blood mononuclear cells, such as toll-like receptors (TLR4), pro-inflammatory cytokines/chemokines interleukin-1 beta, interleukin-6 and monocyte chemoattractant protein-1, and cyclooxygenase-2. Additionally, plasma oleoylethanolamide positively correlated with plasma levels of high mobility group box-1, which is a danger-associated molecular pattern and an endogenous TLR4 agonist, specifically in female alcohol binge drinkers. No changes were observed in 2-acylglycerols in alcohol binge drinkers, although sex-related differences in these bioactive lipids as well as in palmitoleoylethanolamide and docosatetraenoylethanolamide levels were detected. These results extend the previous clinical findings observed in patients diagnosed with long-term alcohol use disorder to young users and suggest a prominent role for these lipids in the response to acute alcohol exposure.Alcohol binge drinkers show, during abstinence, elevations in plasma oleoylethanolamide (OEA), palmitoleoyl ethanolamide (POEA), arachidonoyl ethanolamide (AEA), dihomo-γ-linolenoyl ethanolamide (DGLEA) and palmitoylethanolamide (PEA). These biolipids positively correlate with upregulations in mRNA of toll-like receptor (TLR)-4, interleukin-1 beta, interleukin-6, the monocyte chemoattractant protein-1 or cyclooxygenase-2, which are key inflammatory markers found altered in peripheral blood mononuclear cells of these subjects. Additionally, OEA levels positively correlate with plasma levels of high mobility group box-1, a danger-associated molecular pattern and an endogenous TLR-4 agonist specifically altered in female alcohol binge drinkers.
      PubDate: 2017-11-27T01:15:22.491707-05:
      DOI: 10.1111/adb.12580
  • Environmental enrichment and drug value: a behavioral economic analysis in
           male rats
    • Authors: Justin R. Yates; Michael T. Bardo, Joshua S. Beckmann
      Abstract: Rats raised in an enriched condition (EC) show decreased stimulant self-administration relative to rats reared in an isolated condition (IC). However, few studies have examined the behavioral mechanisms underlying this environment-induced difference in self-administration. Because economic demand for drugs of abuse predicts addiction-like behavior in both humans and animals, we applied a behavioral economic analysis to cocaine self-administration data in EC and IC rats. During cocaine self-administration, the dose decreased across blocks of trials (0.75–0.003 mg/kg/inf), which allowed for a determination of demand intensity and demand elasticity. Demand intensity did not differ between EC and IC rats; however, cocaine was more elastic in EC rats relative to IC rats (i.e. EC rats were less willing to respond for cocaine as the unit price increased). When EC rats were placed in an isolated condition, demand elasticity decreased, whereas elasticity increased for IC rats placed in an enriched condition. Additionally, we applied behavioral economic analyses to previously published self-administration data and found that our results replicate past findings with cocaine and methylphenidate. To determine if differences in demand elasticity are specific to drug reinforcement, a separate group of rats was tested in sucrose or saccharin self-administration. Results showed that sucrose and saccharin were more elastic in EC rats relative to IC rats, and demand intensity was lower for saccharin in EC rats relative to IC rats. Overall, drug and nondrug reinforcers are more elastic in EC rats, which may account for the protective effects of environmental enrichment against stimulant self-administration.Environmental enrichment increases demand elasticity of drug and natural reinforcers (i.e., decreases consumption of these reinforcers as unit price increases). Enriched rats that are placed in an isolated condition show decreased demand elasticity, whereas isolated rats that are placed in an enriched conditioned show increased demand elasticity. Environmental enrichment decreased demand intensity (i.e., consumption of a reinforcer when price is minimally constrained) for saccharin but not for drug reinforcers or for sucrose.
      PubDate: 2017-11-27T01:10:32.069215-05:
      DOI: 10.1111/adb.12581
  • Shared additive genetic variation for alcohol dependence among subjects of
           African and European ancestry
    • Authors: Leslie A. Brick; Matthew C. Keller, Valerie S. Knopik, John E. McGeary, Rohan H.C. Palmer
      Abstract: Alcohol dependence (AD) affects individuals from all racial/ethnic groups, and previous research suggests that there is considerable variation in AD risk between and among various ancestrally defined groups in the United States. Although the reasons for these differences are likely due in part to contributions of complex sociocultural factors, limited research has attempted to examine whether similar genetic variation plays a role across ancestral groups. Using a pooled sample of individuals of African and European ancestry (AA/EA) obtained through data shared within the Database for Genotypes and Phenotypes, we estimated the extent to which additive genetic similarity for AD between AA and EAs using common single nucleotide polymorphisms overlapped across the two populations. AD was represented as a factor score by using Diagnostic and Statistical Manual dependence criteria, and genetic data were imputed by using the 1000 Genomes Reference Panel. Analyses revealed a significant single nucleotide polymorphism-based heritability of 17 percent (SE = 5) in EAs and 24 percent (SE = 15) in AAs. Further, a significant genetic correlation of 0.77 (SE = 0.46) suggests that the allelic architecture influencing the AD factor for EAs and AAs is largely similar across the two populations. Analyses indicated that investigating the genetic underpinnings of alcohol dependence in different ethnic groups may serve to highlight core etiological factors common to both groups and unique etiological factors specific to each ethnic group.We identified similar additive genetic influences on and alcohol dependence factor originating from variants that survive quality control in European and African subjects (Gene Set A), as well as evidence for varied effects from variants that differentially survive quality control across populations (Gene Set B). The alcohol dependence factor represents common phenotypic variance across symptoms (Sx1-7) of dependence based on the Diagnostic and Statistical Manual of Mental Disorders. Note: Diagram represents the conceptual model tested.
      PubDate: 2017-11-27T01:00:36.04899-05:0
      DOI: 10.1111/adb.12578
  • N-Methyl-d-aspartate receptor co-agonist availability affects behavioral
           and neurochemical responses to cocaine: insights into comorbid
           schizophrenia and substance abuse
    • Authors: Matthew D. Puhl; Rajeev I. Desai, Shunsuke Takagi, Kendall T. Presti, Michelle R. Doyle, Rachel J. Donahue, Samantha M. Landino, Jack Bergman, William A. Carlezon, Joseph T. Coyle
      Abstract: Both schizophrenia (SZ) and substance abuse (SA) exhibit significant heritability. Moreover, N-methyl-d-aspartate receptors (NMDARs) have been implicated in the pathophysiology of both SZ and SA. We hypothesize that the high prevalence of comorbid SA in SZ is due to dysfunction of NMDARs caused by shared risk genes. We used transgenic mice with a null mutation of the gene encoding serine racemase (SR), the enzyme that synthesizes the NMDAR co-agonist d-serine and an established risk gene for SZ, to recreate the pathology of SZ. We determined the effect of NMDAR hypofunction resulting from the absence of d-serine on motivated behavior by using intracranial self-stimulation and neurotransmitter release in the nucleus accumbens by using in vivo microdialysis. Compared with wild-type mice, SR−/− mice exhibited similar baseline intracranial self-stimulation thresholds but were less sensitive to the threshold-lowering (rewarding) and the performance-elevating (stimulant) effects of cocaine. While basal dopamine (DA) and glutamate release were elevated in the nucleus accumbens of SR−/− mice, cocaine-induced increases in DA and glutamate release were blunted. γ-Amino-butyric acid efflux was unaffected in the SR−/− mice. Together, these findings suggest that the impaired NMDAR function and a consequent decrease in sensitivity to cocaine effects on behavior are mediated by blunted DA and glutamate responses normally triggered by the drug. Projected to humans, NMDAR hypofunction due to mutations in SR or other genes impacting glutamatergic function in SZ may render abused substances less potent and effective, thus requiring higher doses to achieve a hedonic response, resulting in elevated drug exposure and increased dependence/addiction.The high prevalence of substance abuse in schizophrenia could be due to shared risk genes that impair NMDA receptor function. We studied mice with hypofunctional NMDA receptors caused by genetic inactivation of serine racemase (SR−/− a schizophrenia risk gene. We found that SR−/−mice had decreased sensitivity to cocaine's hedonic effects mediated by blunted accumbens dopamine release. NMDAR hypofunction in schizophrenics may render abused substances less effective, thus requiring higher doses to achieve a hedonic response, resulting in elevated dependence/addiction.
      PubDate: 2017-11-23T04:10:40.715757-05:
      DOI: 10.1111/adb.12577
  • Adolescent ethanol intake alters cannabinoid type-1 receptor localization
           in astrocytes of the adult mouse hippocampus
    • Authors: Itziar Bonilla-Del Rίo; Nagore Puente, Sara Peñasco, Irantzu Rico, Ana Gutiérrez-Rodrίguez, Izaskun Elezgarai, Almudena Ramos, Leire Reguero, Inmaculada Gerrikagoitia, Brian R. Christie, Patrick Nahirney, Pedro Grandes
      Abstract: Cannabinoid type-1 (CB1) receptors are widely distributed in the brain and play important roles in astrocyte function and the modulation of neuronal synaptic transmission and plasticity. However, it is currently unknown how CB1 receptor expression in astrocytes is affected by long-term exposure to stressors. Here we examined CB1 receptors in astrocytes of ethanol (EtOH)-exposed adolescent mice to determine its effect on CB1 receptor localization and density in adult brain. 4–8-week-old male mice were exposed to 20 percent EtOH over a period of 4 weeks, and receptor localization was examined after 4 weeks in the hippocampal CA1 stratum radiatum by pre-embedding immunoelectron microscopy. Our results revealed a significant reduction in CB1 receptor immunoparticles in astrocytic processes of EtOH-exposed mice when compared with controls (positive astrocyte elements: 21.50 ± 2.80 percent versus 37.22 ± 3.12 percent, respectively), as well as a reduction in particle density (0.24 ± 0.02 versus 0.35 ± 0.02 particles/μm). The majority of CB1 receptor metal particles were in the range of 400–1200 nm from synaptic terminals in both control and EtOH. Altogether, the decrease in the CB1 receptor expression in hippocampal astrocytes of adult mice exposed to EtOH during adolescence reveals a long lasting effect of EtOH on astrocytic CB1 receptors. This deficiency may also have negative consequences for synaptic function.CB1 receptors on GFAP-immunoreactive astrocytes in the CA1 stratum radiatum of adult mice were significantly reduced following EtOH exposure during adolescence. However, the CB1 receptor expression on inhibitory synaptic terminals remained unchanged. The low concentration of CB1 receptor immunogold particles on excitatory synaptic terminals in the adult CA1 stratum radiatum also decreased after adolescent EtOH exposure.
      PubDate: 2017-11-23T04:00:48.558622-05:
      DOI: 10.1111/adb.12585
  • Working memory predicts methamphetamine hair concentration over the course
           of treatment: moderating effect of impulsivity and implications for
           dual-systems model
    • Authors: Adam J. Rubenis; Rebecca E. Fitzpatrick, Dan I. Lubman, Antonio Verdejo-Garcia
      Abstract: High impulsivity and poor executive function are characteristic of methamphetamine use disorder. High arousal in the impulsive system has been proposed to compromise the executive system's regulating ability (i.e. the dual-systems model). While interaction between these variables may partly explain poor treatment outcomes associated with methamphetamine use disorder, previous research has tended to examine each factor separately. We investigated whether high impulsivity (measured with an impulsive choice task) and poor executive function (measured with a working memory task) predict methamphetamine use (determined by hair sample) in the 6 weeks following treatment commencement. We also investigated whether impulsive choice moderates the relationship between working memory and methamphetamine use. One hundred and eight individuals with methamphetamine use disorder (75 percent male) were tested within 3 weeks of commencing treatment; 80 (74 percent) were followed up 6 weeks following baseline testing. Cognitive measures significantly predicted drug use after controlling for nuisance variables. Working memory was a significant predictor, while impulsive choice was not. The interaction model included working memory as a predictor and impulsive choice as a moderator. This model was significant, as was the interaction term. Working memory significantly predicted levels of methamphetamine use in early treatment, and impulsive choice moderated this relationship. Those with working memory deficits are particularly vulnerable to using greater amounts of methamphetamine. As working memory increased methamphetamine use decreased among individuals with low/medium delay discounting. Pre-treatment cognitive testing may identify patients at high risk, while remediation of working memory function may be a treatment target for reducing methamphetamine use.We investigated whether behavioural measures of impulsivity (impulsive choice) and executive function (working memory) predict biologically verified methamphetamine use in the 6 weeks following treatment commencement. Working memory emerged as a significant predictor of drug use after controlling for nuisance variables, while impulsive choice significantly moderated this relationship. Working memory deficits may reflect a vulnerability to higher methamphetamine use in early treatment and may be identified with pre-treatment cognitive testing and rehabilitated with cognitive remediation.
      PubDate: 2017-11-08T01:25:25.164492-05:
      DOI: 10.1111/adb.12575
  • Mu opioid receptors in GABAergic neurons of the forebrain promote alcohol
           reward and drinking
    • Authors: Sami Ben Hamida; Laura-Joy Boulos, Michael McNicholas, Pauline Charbogne, Brigitte Lina Kieffer
      Abstract: Mu opioid receptors (MORs) are widely distributed throughout brain reward circuits and their role in drug and social reward is well established. Substantial evidence has implicated MOR and the endogenous opioid system in alcohol reward, but circuit mechanisms of MOR-mediated alcohol reward and intake behavior remain elusive, and have not been investigated by genetic approaches. We recently created conditional knockout (KO) mice targeting the Oprm1 gene in GABAergic forebrain neurons. These mice (Dlx-MOR KO) show a major MOR deletion in the striatum, whereas receptors in midbrain (including the Ventral Tegmental Area or VTA) and hindbrain are intact. Here, we compared alcohol-drinking behavior and rewarding effects in total (MOR KO) and conditional KO mice. Concordant with our previous work, MOR KO mice drank less alcohol in continuous and intermittent two-bottle choice protocols. Remarkably, Dlx-MOR KO mice showed reduced drinking similar to MOR KO mice, demonstrating that MOR in the forebrain is responsible for the observed phenotype. Further, alcohol-induced conditioned place preference was detected in control but not MOR KO mice, indicating that MOR is essential for alcohol reward and again, Dlx-MOR KO recapitulated the MOR KO phenotype. Taste preference and blood alcohol levels were otherwise unchanged in mutant lines. Together, our data demonstrate that MOR expressed in forebrain GABAergic neurons is essential for alcohol reward-driven behaviors, including drinking and place conditioning. Challenging the prevailing VTA-centric hypothesis, this study reveals another mechanism of MOR-mediated alcohol reward and consumption, which does not necessarily require local VTA MORs but rather engages striatal MOR-dependent mechanisms.Our study shows similarly reduced reward-driven alcohol behavior (alcohol drinking and conditioned place preference) in a total knockout mouse model of mu opioid receptor (MOR) and in a conditional knockout deleting MOR majorly in the striatum. Challenging the prevailing ventral tegmental area (VTA)-centric hypothesis, this study reveals another mechanism of MOR-mediated alcohol reward and consumption, which does not necessarily require local VTA MORs but rather engages striatal MOR-dependent mechanisms.
      PubDate: 2017-11-02T02:51:05.110719-05:
      DOI: 10.1111/adb.12576
  • Problematic alcohol use associates with sodium channel and clathrin linker
           1 (SCLT1) in trauma-exposed populations
    • Authors: Lynn M. Almli; Adriana Lori, Jacquelyn L. Meyers, Jaemin Shin, Negar Fani, Adam X. Maihofer, Caroline M. Nievergelt, Alicia K. Smith, Kristina B. Mercer, Kimberly Kerley, Jennifer M. Leveille, Hao Feng, Duna Abu-Amara, Janine D. Flory, Rachel Yehuda, Charles R. Marmar, Dewleen G. Baker, Bekh Bradley, Karestan C. Koenen, Karen N. Conneely, Kerry J. Ressler
      Abstract: Excessive alcohol use is extremely prevalent in the United States, particularly among trauma-exposed individuals. While several studies have examined genetic influences on alcohol use and related problems, this has not been studied in the context of trauma-exposed populations. We report results from a genome-wide association study of alcohol consumption and associated problems as measured by the alcohol use disorders identification test (AUDIT) in a trauma-exposed cohort. Results indicate a genome-wide significant association between total AUDIT score and rs1433375 [N = 1036, P = 2.61 × 10−8 (dominant model), P = 7.76 × 10−8 (additive model)], an intergenic single-nucleotide polymorphism located 323 kb upstream of the sodium channel and clathrin linker 1 (SCLT1) at 4q28. rs1433375 was also significant in a meta-analysis of two similar, but independent, cohorts (N = 1394, P = 0.0004), the Marine Resiliency Study and Systems Biology PTSD Biomarkers Consortium. Functional analysis indicated that rs1433375 was associated with SCLT1 gene expression and cortical-cerebellar functional connectivity measured via resting state functional magnetic resonance imaging. Together, findings suggest a role for sodium channel regulation and cerebellar functioning in alcohol use behavior. Identifying mechanisms underlying risk for problematic alcohol use in trauma-exposed populations is critical for future treatment and prevention efforts.Excessive alcohol use is extremely prevalent in the United States, particularly among trauma-exposed individuals. Our study identifies a novel association between intergenic variant rs1433375 (upstream of SCLT1, a gene associated with the regulation of sodium channel functioning, a putative target of ethanol action) and alcohol use behavior in a community cohort of African Americans with high levels of trauma exposure. We show converging data for the role of a sodium channel regulator from the genotypic, expression-based, and functional neuroimaging findings, which provide support for these mechanistic pathways in alcohol use and related behaviors.
      PubDate: 2017-10-30T00:01:02.350349-05:
      DOI: 10.1111/adb.12569
  • Inhibition of fatty acid amide hydrolase in the central amygdala
           alleviates co-morbid expression of innate anxiety and excessive alcohol
    • Authors: Serena Stopponi; Yannick Fotio, Ana Domi, Anna Maria Borruto, Luis Natividad, Marisa Roberto, Roberto Ciccocioppo, Nazzareno Cannella
      Abstract: Fatty acid amide hydrolase (FAAH) is an enzyme that prominently degrades the major endocannabinoid N-arachidonoylethanolamine (anandamide). Inhibition of this enzyme leads to increased anandamide levels in brain regions that modulate stress and anxiety. Recently, we found that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats display hyperactive FAAH in amygdalar regions that was associated with increased stress sensitivity and a hyper-anxious phenotype. Our previous work has also demonstrated that msPs display an innate preference for and excessive consumption of alcohol, potentially reflecting a form of self-medication to gain relief from hyper-anxious states. Here, we expand on our previous work by microinjecting the selective FAAH inhibitor URB597 (vehicle, 0.03, 0.1 and 1.0 μg per rat) into the central amygdala (CeA) and basolateral amygdala in msP versus non-selected Wistar rats to evaluate the effects of localized FAAH inhibition on operant alcohol self-administration and restraint-induced anxiety using the elevated plus maze. Intra-CeA URB597 significantly reduced alcohol self-administration in msP but not in Wistar rats. Intra-basolateral amygdala URB597 also attenuated alcohol drinking in msPs, although the effect was less pronounced relative to CeA treatment. In contrast, control experiments administering URB597 into the ventral tegmental area produced no genotypic differences in drinking. We also found that URB597 treatment in the CeA significantly reduced the anxiogenic effects of restraint stress in msPs, although no effects were detected in Wistars. Dysregulation of FAAH regulated systems in the major output region of the amygdala may drive the propensity for co-morbid expression of anxiety and excessive alcohol use.Hyperactive fatty acid amide hydrolase (FAAH) in amygdalar regions is associated with increased stress sensitivity and a hyper-anxious phenotype in genetically selected alcohol-preferring msP rats. Central amygdala administration of the selective FAAH inhibitor URB597 reduces alcohol self-administration and stress-induced anxiety in msP, but not Wistar rats.
      PubDate: 2017-10-26T00:00:25.204035-05:
      DOI: 10.1111/adb.12573
  • Genome-wide association study of alcohol use disorder identification test
           (AUDIT) scores in 20 328 research participants of European ancestry
    • Authors: Sandra Sanchez-Roige; Pierre Fontanillas, Sarah L. Elson, , Joshua C. Gray, Harriet Wit, Lea K. Davis, James MacKillop, Abraham A. Palmer
      Abstract: Genetic factors contribute to the risk for developing alcohol use disorder (AUD). In collaboration with the genetics company 23andMe, Inc., we performed a genome-wide association study of the alcohol use disorder identification test (AUDIT), an instrument designed to screen for alcohol misuse over the past year. Our final sample consisted of 20 328 research participants of European ancestry (55.3% females; mean age = 53.8, SD = 16.1) who reported ever using alcohol. Our results showed that the ‘chip-heritability’ of AUDIT score, when treated as a continuous phenotype, was 12%. No loci reached genome-wide significance. The gene ADH1C, which has been previously implicated in AUD, was among our most significant associations (4.4 × 10−7; rs141973904). We also detected a suggestive association on chromosome 1 (2.1 × 10−7; rs182344113) near the gene KCNJ9, which has been implicated in mouse models of high ethanol drinking. Using linkage disequilibrium score regression, we identified positive genetic correlations between AUDIT score, high alcohol consumption and cigarette smoking. We also observed an unexpected positive genetic correlation between AUDIT and educational attainment and additional unexpected negative correlations with body mass index/obesity and attention-deficit/hyperactivity disorder. We conclude that conducting a genetic study using responses to an online questionnaire in a population not ascertained for AUD may represent a cost-effective strategy for elucidating aspects of the etiology of AUD.We performed a genome-wide association study of the Alcohol Use Disorder Identification Test (AUDIT) using 20 328 research participants of European ancestry. No loci reached genome-wide significance. An SNP near the gene ADH1C was among our most significant associations (4.4 × 10−7; rs141973904); this locus has been previously implicated in both alcoholism and alcohol consumption. We identified positive genetic correlations between AUDIT and multiple traits, including alcohol consumption and smoking initiation.
      PubDate: 2017-10-23T05:25:31.330462-05:
      DOI: 10.1111/adb.12574
  • Association of the alcohol dehydrogenase gene polymorphism rs1789891 with
           gray matter brain volume, alcohol consumption, alcohol craving and relapse
    • Authors: Patrick Bach; Vagelis Zois, Sabine Vollstädt-Klein, Martina Kirsch, Sabine Hoffmann, Anne Jorde, Josef Frank, Katrin Charlet, Jens Treutlein, Anne Beck, Andreas Heinz, Henrik Walter, Marcella Rietschel, Falk Kiefer
      Abstract: Alcohol metabolizing enzymes, such as the alcohol dehydrogenases and the aldehyde dehydrogenases, regulate the levels of acetaldehyde in the blood and play an important role in the development and maintenance of alcohol addiction. Recent genome-wide systematic searches found associations between a single nucleotide polymorphism (rs1789891, risk allele: A, protective allele: C) in the alcohol dehydrogenase gene cluster and the risk of alcohol dependence. The current study investigated the effect of this single nucleotide polymorphism on alcohol consumption, craving for alcohol, relapse risk and brain gray matter volume. Alcohol-dependent patients (n = 74) and controls (n = 43) were screened, genotyped and underwent magnetic resonance imaging scanning, and relapse data were collected during 3 months following the experiment. Alcohol-dependent A allele carriers reported increased alcohol craving and higher alcohol consumption compared with the group of alcohol-dependent individuals homozygous for the C allele, which displayed craving values similar to the control group. Further, follow-up data indicated that A allele carriers relapsed earlier to heavy drinking compared with individuals with two C alleles. Analyses of gray matter volume indicated a significant genotype difference in the patient group: individuals with two C alleles had reduced gray matter volume in the left and right superior, middle and inferior temporal gyri.Findings of the current study further support the relevance of genetic variants in alcohol metabolizing enzymes to addictive behavior, brain tissue volume and relapse risk. Genotype-dependent differences in acetaldehyde formation, implicated by earlier studies, might be the biological substrate of the genotype differences.This study presents initial evidence that a genetic polymorphism in the alcohol dehydrogenase gene cluster (rs1789891), which was associated with alcohol dependence risk before, is associated with increased alcohol cue-induced craving, higher alcohol consumption, gray matter volume loss in bilateral temporal gyri and higher relapse risk in alcohol dependent patients.
      PubDate: 2017-10-23T04:55:32.458497-05:
      DOI: 10.1111/adb.12571
  • Orbitofrontal gray matter deficits as marker of Internet gaming disorder:
           converging evidence from a cross-sectional and prospective longitudinal
    • Authors: Feng Zhou; Christian Montag, Rayna Sariyska, Bernd Lachmann, Martin Reuter, Bernd Weber, Peter Trautner, Keith M. Kendrick, Sebastian Markett, Benjamin Becker
      Abstract: Internet gaming disorder represents a growing health issue. Core symptoms include unsuccessful attempts to control the addictive patterns of behavior and continued use despite negative consequences indicating a loss of regulatory control. Previous studies revealed brain structural deficits in prefrontal regions subserving regulatory control in individuals with excessive Internet use. However, because of the cross-sectional nature of these studies, it remains unknown whether the observed brain structural deficits preceded the onset of excessive Internet use. Against this background, the present study combined a cross-sectional and longitudinal design to determine the consequences of excessive online video gaming. Forty-one subjects with a history of excessive Internet gaming and 78 gaming-naive subjects were enrolled in the present study. To determine effects of Internet gaming on brain structure, gaming-naive subjects were randomly assigned to 6 weeks of daily Internet gaming (training group) or a non-gaming condition (training control group). At study inclusion, excessive Internet gamers demonstrated lower right orbitofrontal gray matter volume compared with Internet gaming-naive subjects. Within the Internet gamers, a lower gray matter volume in this region was associated with higher online video gaming addiction severity. Longitudinal analysis revealed initial evidence that left orbitofrontal gray matter volume decreased during the training period in the training group as well as in the group of excessive gamers. Together, the present findings suggest an important role of the orbitofrontal cortex in the development of Internet addiction with a direct association between excessive engagement in online gaming and structural deficits in this brain region.The present study combined a cross-sectional and prospective longitudinal design to determine brain structural consequences of excessive Internet gaming. Cross-sectional comparisons revealed reduced right orbitofrontal gray matter volume in excessive Internet gamers; longitudinal comparisons revealed decreased left orbitofrontal gray matter volume during 6 weeks of regular Internet gaming, in both excessive gamers and (at study inclusion) gaming-naive subjects. Together, the convergent findings suggest that excessive Internet gaming induces gray matter reductions in the orbitofrontal cortex.
      PubDate: 2017-10-23T02:15:24.93376-05:0
      DOI: 10.1111/adb.12570
  • Selective inhibition of M5 muscarinic acetylcholine receptors attenuates
           cocaine self-administration in rats
    • Authors: Barak W. Gunter; Robert W. Gould, Michael Bubser, Kevin M. McGowan, Craig W. Lindsley, Carrie K. Jones
      Abstract: Cocaine use disorder (CUD) remains a debilitating health problem in the United States for which there are no Food and Drug Administration-approved treatment options. Accumulating anatomical and electrophysiological evidence indicates that the muscarinic acetylcholine receptor (mAChR) subtype 5 (M5) plays a critical role in the regulation of the mesolimbic dopaminergic reward circuitry, a major site of action for cocaine and other psychostimulants. In addition, M5 knockout mice exhibit reduced cocaine self-administration behaviors with no differences in sugar pellet-maintained responding relative to wild-type mice. These findings suggest that selective inhibition of M5 mAChR may provide a novel pharmacological approach for targeting CUD. Recently, we reported the synthesis and characterization of ML375, a selective negative allosteric modulator (NAM) for the rat and human M5 mAChR with optimized pharmacokinetic properties for systemic dosing in rodents. In the present study, male Sprague–Dawley rats were trained to self-administer intravenous cocaine (0.1–0.75 mg/kg/infusion) under a 10-response fixed ratio or a progressive ratio schedule of reinforcement. Under both schedules of reinforcement, ML375 produced dose-related reductions in cocaine self-administration. ML375 also modestly reduced sugar pellet-maintained responding on the 10-response, fixed ratio schedule but had no effect under a progressive ratio schedule of reinforcement. Further, ML375 did not affect general motor output as assessed by a rotarod test. Collectively, these results provide the first demonstration that selective inhibition of M5 using the M5 NAM ML375 can attenuate both the reinforcing effects and the relative strength of cocaine and suggest that M5 NAMs may represent a promising, novel treatment approach for CUD.The first in class, selective muscarinic receptor subtype 5 (M5) negative allosteric modulator, ML375 reduces the reinforcing efficacy of cocaine in rats, without affecting sucrose pellet-maintained responding. Furthermore, ML375 has no effect on rotarod performance. This study shows for the first time that selective modulation of M5 may be a novel therapeutic strategy for the treatment of cocaine use disorder.
      PubDate: 2017-10-18T03:00:27.09338-05:0
      DOI: 10.1111/adb.12567
  • Activated mesenchymal stem cell administration inhibits chronic alcohol
           drinking and suppresses relapse-like drinking in high-alcohol drinker rats
    • Authors: Fernando Ezquer; María Elena Quintanilla, Paola Morales, Marcelo Ezquer, Carolyne Lespay-Rebolledo, Mario Herrera-Marschitz, Yedy Israel
      Abstract: Neuroinflammation has been reported to follow chronic ethanol intake and may perpetuate alcohol consumption. Present studies determined the effect of human mesenchymal stem cells (hMSCs), known for their anti-inflammatory action, on chronic ethanol intake and relapse-like ethanol intake in a post-deprivation condition. Rats were allowed 12–17 weeks of chronic voluntary ethanol (10% and 20% v/v) intake, after which a single dose of activated hMSCs (5 × 105) was injected into a brain lateral ventricle. Control animals were administered vehicle. After assessing the effect of hMSCs on chronic ethanol intake for 1 week, animals were deprived of ethanol for 2 weeks and thereafter an ethanol re-access of 60 min was allowed to determine relapse-like intake. A single administration of activated hMSCs inhibited chronic alcohol consumption by 70% (P 
      PubDate: 2017-10-18T01:05:53.626092-05:
      DOI: 10.1111/adb.12572
  • Hypocretin receptor 1 knockdown in the ventral tegmental area attenuates
           mesolimbic dopamine signaling and reduces motivation for cocaine
    • Authors: David L. Bernstein; Preeti S. Badve, Jessica R. Barson, Caroline E. Bass, Rodrigo A. España
      Abstract: The hypocretin receptor 1 (HCRTr1) is a critical participant in the regulation of motivated behavior. Previous observations demonstrate that acute pharmacological blockade of HCRTr1 disrupts dopamine (DA) signaling and the motivation for cocaine when delivered systemically or directly into the ventral tegmental area (VTA). To further examine the involvement of HCRTr1 in regulating reward and reinforcement processing, we employed an adeno-associated virus to express a short hairpin RNA designed to knock down HCRTr1. We injected virus into the VTA and examined the effects of HCRTr1 knockdown on cocaine self-administration and DA signaling in the nucleus accumbens (NAc) core. We determined that the viral approach was effective at reducing HCRTr1 expression without affecting the expression of hypocretin receptor 2 or DA-related mRNAs. We next examined the effects of HCRTr1 knockdown on cocaine self-administration, observing delayed acquisition under a fixed-ratio schedule and reduced motivation for cocaine under a progressive ratio schedule. These effects did not appear to be associated with alterations in sleep/wake activity. Using fast-scan cyclic voltammetry, we then examined whether HCRTr1 knockdown alters DA signaling dynamics in the NAc core. We observed reduced DA release and slower uptake rate as well as attenuated cocaine-induced DA uptake inhibition in rats with knockdown of HCRTr1. These observations indicate that HCRTr1 within the VTA influence the motivation for cocaine, likely via alterations in DA signaling in the NAc.To examine the involvement of hypocretin receptor 1 in regulating reward and reinforcement, we employed shRNA viruses to knock down the expression of hypocretin receptor 1 specifically in the ventral tegmental area. Results indicate that hypocretin receptor 1 knockdown disrupts cocaine self-administration behavior and attenuates dopamine responses to cocaine in the nucleus accumbens core. These observations indicate that hypocretin receptor 1 within the ventral tegmental area is essential for supporting motivation for cocaine likely via actions on the mesolimbic dopamine system.
      PubDate: 2017-10-02T22:06:01.192024-05:
      DOI: 10.1111/adb.12553
  • Minocycline increases firing rates of accumbal neurons and modifies the
           effects of morphine on neuronal activity
    • Authors: Reza Arezoomandan; Esmail Riahi, Abbas Haghparast
      Abstract: Accumulating evidence indicated that minocycline, a glial cell modulator, is able to modify a variety of morphine effects. Here, we investigated minocycline effects on electrical activity of nucleus accumbens (NAc) neurons using single unit recording in urethane-anesthetized rats. In addition, we investigated whether minocycline can modify the effects of morphine on NAc neural activity during reinstatement of morphine-seeking behavior. Minocycline increased the NAc firing activity in intact animals. Electrophysiological recording in morphine-treated animals was performed, following the acquisition of morphine-induced conditioned place preference (5 mg/kg, s.c., 3 days) and a drug-free extinction period. In acutely minocycline- treated animals, the neurons were recorded for 40 minutes following a single injection of either minocycline (50 μg/5 μl, i.c.v.) or saline. Then a priming dose of morphine (1 mg/kg, s.c.) was injected while the recording was continued for an additional 40 minutes. Minocycline significantly increased the firing rates of neurons and significantly modified morphine inhibitory effects on NAc neurons. In subchronically minocycline-treated groups, the rats were given daily injections of minocycline (50 μg/5 μl, i.c.v) during the extinction period. Then, on the reinstatement day, NAc neurons were recorded for 10 minutes, the priming dose of morphine was administered and the recording was continued for 45 minutes. Our results showed the failure of minocycline to significantly modify the inhibitory effects of morphine. In conclusion, our findings indicated that minocycline modifies morphine-induced decreases in the firing rates of NAc neurons in the reinstatement phase.Intra-LV injection of minocycline increases NAc neural activity. Intra-LV infusion of minocycline modifies the inhibitory effects of morphine on NAc neurons. Subchronic minocycline infusions during extinction phase dose not modify the inhibitory effects of morphine on NAc neurons.
      PubDate: 2017-09-29T11:36:43.1731-05:00
      DOI: 10.1111/adb.12557
  • Functional role for suppression of the insular–striatal circuit in
           modulating interoceptive effects of alcohol
    • Authors: Anel A. Jaramillo; Verda E. Agan, Viren H. Makhijani, Stephen Pedroza, Zoe A. McElligott, Joyce Besheer
      Abstract: The insular cortex (IC) is a region proposed to modulate, in part, interoceptive states and motivated behavior. Interestingly, IC dysfunction and deficits in interoceptive processing are often found among individuals with substance-use disorders. Furthermore, the IC projects to the nucleus accumbens core (AcbC), a region known to modulate the discriminative stimulus/interoceptive effects of alcohol and other drug-related behaviors. Therefore, the goal of the present work was to investigate the possible role of the IC ➔ AcbC circuit in modulating the interoceptive effects of alcohol. Thus, we utilized a chemogenetic technique (hM4Di designer receptor activation by designer drugs) to silence neuronal activity in the IC of rats trained to discriminate alcohol (1 g/kg, IG) versus water using an operant or Pavlovian alcohol discrimination procedure. Chemogenetic silencing of the IC or IC ➔ AcbC neuronal projections resulted in potentiated sensitivity to the interoceptive effects of alcohol in both the operant and Pavlovian tasks. Together, these data provide critical evidence for the nature of the complex IC circuitry and, specifically, suppression of the insular–striatal circuit in modulating behavior under a drug stimulus control.We examined the insular cortex (IC) and its projections to the nucleus accumbens core (AcbC) in modulating the interoceptive effects of alcohol in two alcohol discrimination tasks (operant and Pavlovian) in rats. Silencing IC ➔ AcbC projections (using chemogenetics) potentiated the effects of alcohol and produced ‘alcohol-like’ effects. This increased sensitivity to alcohol was more pronounced than silencing the IC alone. These findings show the critical nature of IC circuitry in an alcohol drug state, which can have implications for drinking/seeking behaviors. CNO, clozapine-n-oxide
      PubDate: 2017-09-27T04:01:36.878663-05:
      DOI: 10.1111/adb.12551
  • Limited potential of cebranopadol to produce opioid-type physical
           dependence in rodents
    • Authors: Thomas M. Tzschentke; Babette Y. Kögel, Stefanie Frosch, Klaus Linz
      Abstract: Cebranopadol is a novel potent analgesic agonist at the nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors. As NOP receptor activation has been shown to reduce side effects related to the activation of μ-opioid peptide (MOP) receptors, the present study evaluated opioid-type physical dependence produced by cebranopadol in mice and rats. In a naloxone-precipitated withdrawal assay in mice, a regimen of seven escalating doses of cebranopadol over 2 days produced only very limited physical dependence as evidenced by very little withdrawal symptoms (jumping) even at cebranopadol doses clearly exceeding the analgesic dose range. In contrast, mice showed clear withdrawal symptoms when treated with morphine within the analgesic dose range. In the rat, spontaneous withdrawal (by cessation of drug treatment; in terms of weight loss and behavioral score) was studied after 4-week subacute administration. Naloxone-precipitated withdrawal (in terms of weight loss and behavioral score) was studied in the same groups of rats after 1-week re-administration following the spontaneous withdrawal period. In both tests, cebranopadol-treated rats showed only few signs of withdrawal, while withdrawal effects in rats treated with morphine were clearly evident. These findings demonstrate a low potential of cebranopadol to produce opioid-type physical dependence in rodents. The prospect of this promising finding into the clinical setting remains to be established.In two rodent dependence/withdrawal models, opioid-type physical dependence produced by cebranopadol, a novel potent analgesic agonist at the nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors, was studied. Cebranopadol-treated animals showed clearly less spontaneous and precipitated withdrawal (jumping, body weight loss and behavioral score) as compared with morphine-treated animals. These findings demonstrate a low potential of cebranopadol to produce opioid-type physical dependence in rodents. The prospect of this promising finding into the clinical setting remains to be established.
      PubDate: 2017-09-25T02:40:33.865888-05:
      DOI: 10.1111/adb.12550
  • Imaging the neuroimmune response to alcohol exposure in adolescent
           baboons: a TSPO PET study using 18F-DPA-714
    • Authors: Wadad Saba; Sébastien Goutal, Sylvain Auvity, Bertrand Kuhnast, Christine Coulon, Virginie Kouyoumdjian, Irène Buvat, Claire Leroy, Nicolas Tournier
      Abstract: The effects of acute alcohol exposure to the central nervous system are hypothesized to involve the innate immune system. The neuroimmune response to an initial and acute alcohol exposure was investigated using translocator protein 18 kDa (TSPO) PET imaging, a non-invasive marker of glial activation, in adolescent baboons. Three different alcohol-naive adolescent baboons (3–4 years old, 9 to 14 kg) underwent 18F-DPA-714 PET experiments before, during and 7–12 months after this initial alcohol exposure (0.7–1.0 g/l). The brain distribution of 18F-DPA-714 (VT; in ml/cm3) was estimated in several brain regions using the Logan plot analysis and the metabolite-corrected arterial input function. Compared with alcohol-naive animals (VTbrain = 3.7 ± 0.7 ml/cm3), the regional VTs of 18F-DPA-714 were significantly increased during alcohol exposure (VTbrain = 7.2 ± 0.4 ml/cm3; p 
      PubDate: 2017-09-25T02:16:35.307902-05:
      DOI: 10.1111/adb.12548
  • Red Bull® energy drink increases consumption of higher concentrations
           of alcohol
    • Authors: Marta Roldán; Victor Echeverry-Alzate, Kora-Mareen Bühler, Israel J. Sánchez-Diez, Javier Calleja-Conde, Pedro Olmos, Stephen L. Boehm, Rafael Maldonado, Fernando Rodríguez de Fonseca, Catalina Santiago, Felix Gómez-Gallego, Elena Giné, Jose Antonio López-Moreno
      Abstract: Mixing alcohol with caffeinated energy drinks is a common practice, especially among young people. In humans, the research on this issue has mainly focused on the use of the mass-marketed energy drinks themselves, whereas in animal models, it has focused on the individual effects of their active ingredients (i.e. caffeine). Here, we have characterized how Red Bull®, one of the most consumed caffeinated energy drink worldwide, modulates operant alcohol self-administration in Wistar rats. We found that animals readily and steadily responded for Red Bull (mean: 90 responses, 30 minutes and fixed-ratio 1), which was accompanied by locomotor stimulating effects (26 percent increase). The higher the concentration of alcohol (3–20 percent), the higher the consumption of alcohol (g/kg) and associated blood alcohol levels (91.76 percent) in the mixed Red Bull–alcohol group (60 percent increase). Blood caffeine levels in the Red Bull group were 4.69 μg/ml and 1.31 μg/ml in the Red Bull–alcohol group after the 30-minute session. Because Red Bull also contains 11 percent sucrose, we examined the time course of blood glucose as well as insulin and corticosterone. The correlation between intake of Red Bull and blood glucose levels was higher at 90 minutes than 5 minutes after its consumption, and there was no relationship with blood insulin or blood corticosterone levels. Red Bull did not alter extinction and reacquisition of responding for alcohol nor did it affect relapse-like drinking. Overall, our results suggest that Red Bull might be a vulnerability factor to develop alcoholism given that it intensifies the consumption of higher concentrations of alcohol.Wistar rats will readily self-administer Red Bull® in an operant self-administration paradigm. After Red Bull® is mixed with alcohol, animals show an increased self-administration response for higher concentrations of alcohol; that is, the higher the alcohol concentration in the alcohol–Red Bull ® mix, the higher the alcohol consumption. Highly caffeinated energy drinks like Red Bull® might be a vulnerability factor to develop alcoholism by intensifying the consumption of higher concentrations of alcohol.
      PubDate: 2017-09-22T05:45:54.463141-05:
      DOI: 10.1111/adb.12560
  • Amino acid modulation of dopamine in the nucleus accumbens mediates sex
           differences in nicotine withdrawal
    • Authors: Luis M. Carcoba; Rodolfo J. Flores, Luis A. Natividad, Laura E. O'Dell
      Abstract: The aversive effect of nicotine withdrawal is greater in female versus male rats, and we postulate that this sex difference is mediated in the nucleus accumbens (NAc). Nicotine withdrawal induces decreases in NAc dopamine and increases in acetylcholine (ACh) levels in male rats. To our knowledge, these neurochemical markers of nicotine withdrawal have not been compared in female versus male rats. Given the role of amino acids in modulating NAc dopaminergic and cholinergic transmission, concomitant measures of gamma-aminobutyric acid (GABA) and glutamate levels were also compared across sex. Rats received continuous nicotine exposure for 14 days, and then NAc dialysate was collected during baseline and following administration of the nicotinic receptor antagonist mecamylamine to precipitate withdrawal. Chronic nicotine exposure was associated with larger increases in baseline dopamine, GABA and glutamate levels in the NAc of female versus male rats, whereas baseline ACh was only increased in male rats. During withdrawal, both sexes displayed equivalent increases in NAc ACh levels. As expected, male rats displayed decreases in dopamine, coupled with increases in GABA and decreases in glutamate levels, suggesting the possibility of increased inhibitory tone in the NAc during withdrawal. Relative to males, female rats displayed larger decreases in NAc dopamine and related increases in GABAergic transmission. As female rats also showed elevated glutamate levels that persist during withdrawal, it is suggested that sex differences may arise from increased glutamatergic drive of inhibitory tone in the NAc. The findings provide a potential mechanism whereby the aversive effects of nicotine withdrawal are enhanced in female rats.It is suggested that the aversive effects of nicotine withdrawal are greater in female rats. Our results show that during nicotine withdrawal, female rats display larger decreases in NAc dopamine and increased gamma-aminobutyric acid (GABA)ergic transmission relative to male rats. Female rats also show elevated glutamate levels that persist during withdrawal, suggesting that sex differences may arise from an increased glutamatergic drive of inhibitory tone in the nucleus accumbens. The findings provide a potential mechanism whereby the aversive effects of nicotine withdrawal are enhanced in female rats.
      PubDate: 2017-09-22T05:35:56.339953-05:
      DOI: 10.1111/adb.12556
  • Time-dependent neuronal changes associated with craving in opioid
           dependence: an fMRI study
    • Authors: Anna Murphy; Dan I. Lubman, Shane McKie, Prun S. Bijral, Lesley A. Peters, Qasim Faiz, Sophie E. Holmes, Ian M. Anderson, Bill Deakin, Rebecca Elliott
      Abstract: Relapse after initially successful treatment is a significant problem facing the treatment of opioid dependence. Evidence suggests craving elicited by re-exposure to drug cues may precipitate relapse. Attempts to identify neural biomarkers of cue-elicited craving have yielded inconsistent findings. We aimed to apply a novel continuous functional magnetic resonance imaging technique to follow the minute-to-minute evolution of brain responses, which correlate with the waxing and waning of craving. Newly detoxified male opioid-dependent patients and healthy control participants attended two separate, counterbalanced, functional magnetic resonance imaging scanning sessions during which they viewed a 10-minute video (drug cue or neutral cue) followed by 5 minutes of fixation. Participants rated the intensity of their craving throughout each session. We hypothesized that subcortical/ventral prefrontal cortex (PFC) regions and dorsal PFC regions would show different associations with craving reflecting their putative roles in appetitive processing versus cognitive control. Compared with controls, drug cue (minus neutral cue) video recruited the left amygdala and was temporally correlated with craving. In contrast, dorsal anterior cingulate blood-oxygen-level-dependent signal time course was higher than controls only during a period after cue exposure when craving levels were declining. Against expectations, neither the ventral striatum nor ventral PFC was significantly recruited by drug cue exposure. Findings suggest that the amygdala has a central role in craving, whereas the dorsal anterior cingulate may control craving in treatment-seeking patients. Time course analysis yielded new insights into the neural substrates of craving that could objectively validate development of psychological and pharmacological approaches to sustained abstinence.Time course fMRI analysis in newly abstinent opioid participant (blue line; red dotted line shows control participants) during a period of video cue exposure demonstrated the left amygdala correlated with craving time course. In contrast, greatest recruitment of the dorsal anterior cingulate occurred when craving levels were declining. This suggests a central role of amygdala in craving generation and the dorsal anterior cingulate in craving control.
      PubDate: 2017-09-22T05:25:28.257586-05:
      DOI: 10.1111/adb.12554
  • Phosphorylation of calcium/calmodulin-dependent protein kinase II in the
           rat dorsal medial prefrontal cortex is associated with alcohol-induced
           cognitive inflexibility
    • Authors: Luis A. Natividad; Michael Q. Steinman, Sarah A. Laredo, Cristina Irimia, Ilham Y. Polis, Robert Lintz, Matthew W. Buczynski, Rémi Martin-Fardon, Marisa Roberto, Loren H. Parsons
      Abstract: Repeated cycles of alcohol [ethanol (EtOH)] intoxication and withdrawal dysregulate excitatory glutamatergic systems in the brain and induce neuroadaptations in the medial prefrontal cortex (mPFC) that contribute to cognitive dysfunction. The mPFC is composed of subdivisions that are functionally distinct, with dorsal regions facilitating drug-cue associations and ventral regions modulating new learning in the absence of drug. A key modulator of glutamatergic activity is the holoenzyme calcium/calmodulin-dependent protein kinase II (CaMKII) that phosphorylates ionotropic glutamate receptors. Here, we examined the hypothesis that abstinence from chronic intermittent EtOH (CIE) exposure dysregulates CaMKII activity in the mPFC to impair cognitive flexibility. We used an operant model of strategy set shifting in male Long–Evans rats demonstrating reduced susceptibility to trial omissions during performance in a visual cue-guided task versus albino strains. Relative to naïve controls, rats experiencing approximately 10 days of abstinence from CIE vapor exposure demonstrated impaired performance during a procedural shift from visual cue to spatial location discrimination. Phosphorylation of CaMKII subtype α was upregulated in the dorsal, but not ventral mPFC of CIE-exposed rats, and was positively correlated with perseverative-like responding during the set shift. The findings suggest that abstinence from CIE exposure induces an undercurrent of kinase activity (e.g. CaMKII), which may promote aberrant glutamatergic responses in select regions of the mPFC. Given the role of the mPFC in modulating executive control of behavior, we propose that increased CaMKII subtype α activity reflects a dysregulated ‘top-down’ circuit that interferes with adaptive behavioral performance under changing environmental demands.Cognitive impairments are a hallmark characteristic of alcoholism associated with dysregulated excitatory signaling in the medial prefrontal cortex (mPFC). Here, we report a parsing of function in the mPFC of alcohol-dependent rats involving calcium/calmodulin-dependent protein kinase II (CaMKII). Specifically, increased phosphorylation of CaMKII(α)* in the dorsal mPFC aligned with key deficits in behavioral flexibility during alcohol abstinence. The findings are discussed in terms of methodological considerations, phenotypic characteristics of cognitive dysfunction and mechanisms promoting aberrant glutamatergic function during abstinence.
      PubDate: 2017-09-22T05:21:16.732389-05:
      DOI: 10.1111/adb.12568
  • α6 subunit-containing nicotinic receptors mediate low-dose ethanol
           effects on ventral tegmental area neurons and ethanol reward
    • Authors: Scott C. Steffensen; Samuel I. Shin, Ashley C. Nelson, Stephanie S. Pistorius, Stephanie B. Williams, Taylor J. Woodward, Hyun Jung Park, Lindsey Friend, Ming Gao, Fenfei Gao, Devin H. Taylor, M. Foster Olive, Jeffrey G. Edwards, Sterling N. Sudweeks, Lori M. Buhlman, J. Michael McIntosh, Jie Wu
      Abstract: Dopamine (DA) neuron excitability is regulated by inhibitory GABAergic synaptic transmission and modulated by nicotinic acetylcholine receptors (nAChRs). The aim of this study was to evaluate the role of α6 subunit-containing nAChRs (α6*-nAChRs) in acute ethanol effects on ventral tegmental area (VTA) GABA and DA neurons. α6*-nAChRs were visualized on GABA terminals on VTA GABA neurons, and α6*-nAChR transcripts were expressed in most DA neurons, but only a minority of VTA GABA neurons from GAD67 GFP mice. Low concentrations of ethanol (1–10 mM) enhanced GABAA receptor (GABAAR)-mediated spontaneous and evoked inhibition with blockade by selective α6*-nAChR antagonist α-conotoxins (α-Ctxs) and lowered sensitivity in α6 knock-out (KO) mice. Ethanol suppression of VTA GABA neuron firing rate in wild-type mice in vivo was significantly reduced in α6 KO mice. Ethanol (5–100 mM) had no effect on optically evoked GABAAR-mediated inhibition of DA neurons, and ethanol enhancement of VTA DA neuron firing rate at high concentrations was not affected by α-Ctxs. Ethanol conditioned place preference was reduced in α6 KO mice compared with wild-type controls. Taken together, these studies indicate that relatively low concentrations of ethanol act through α6*-nAChRs on GABA terminals to enhance GABA release onto VTA GABA neurons, in turn to reduce GABA neuron firing, which may lead to VTA DA neuron disinhibition, suggesting a possible mechanism of action of alcohol and nicotine co-abuse.GABA (GAD67 GFP: green) terminals (VGAT: blue) on VTA GABA neurons co-express α6*nAChRs (α-Ctx MII: red). Single-cell, quantitative real-time PCR revealed that a subpopulation of GABA neurons in the VTA express α6*nAChRs. Our findings indicate that low concentrations of ethanol act through α6*-nAChRs on GABA terminals to enhance GABA release onto VTA GABA neurons, in turn to reduce GABA neuron firing, which may lead to VTA DA neuron disinhibition, suggesting a possible mechanism of action of alcohol and nicotine co-abuse.
      PubDate: 2017-09-13T02:20:48.169204-05:
      DOI: 10.1111/adb.12559
  • Abnormal gray matter volume and impulsivity in young adults with Internet
           gaming disorder
    • Authors: Deokjong Lee; Kee Namkoong, Junghan Lee, Young-Chul Jung
      Abstract: Reduced executive control is one of the central components of model on the development and maintenance of Internet gaming disorder (IGD). Among the various executive control problems, high impulsivity has consistently been associated with IGD. We performed voxel-based morphometric analysis with diffeomorphic anatomical registration by using an exponentiated Lie algebra algorithm (DARTEL) to investigate the relationship of gray matter abnormalities to impulsivity in IGD. Thirty-one young male adults whose excessive Internet gaming began in early adolescence, and 30 age-matched male healthy controls were examined. IGD subjects showed smaller gray matter volume (GMV) in brain regions implicated in executive control, such as the anterior cingulate cortex and the supplementary motor area. The GMVs in the anterior cingulate cortex and the supplementary motor area were negatively correlated with self-reporting scales of impulsiveness. IGD subjects also exhibited smaller GMV in lateral prefrontal and parietal cortices comprising the left ventrolateral prefrontal cortex and the left inferior parietal lobule when compared with healthy controls. The GMVs in the left ventrolateral prefrontal cortex were negatively correlated with lifetime usage of Internet gaming. These findings suggest that gray matter abnormalities in areas related to executive control may contribute to high impulsivity of young adults with IGD. Furthermore, alterations in the prefrontal cortex were related with long-term excessive Internet gaming during adolescence.Young males with Internet gaming disorder showed smaller gray matter volume in executive control-related brain regions including the anterior cingulate cortex and the ventrolateral prefrontal cortex. Lower gray matter volume in the anterior cingulate cortex correlated with higher impulsivity. Lower gray matter volume in the ventrolateral prefrontal cortex correlated with longer lifetime usage of Internet gaming.
      PubDate: 2017-09-08T06:25:33.422908-05:
      DOI: 10.1111/adb.12552
  • Cafeteria diet induces neuroplastic modifications in the nucleus accumbens
           mediated by microglia activation
    • Authors: Miriam Gutiérrez-Martos; Benoit Girard, Sueli Mendonça-Netto, Julie Perroy, Emmanuel Valjent, Rafael Maldonado, Miquel Martin
      Abstract: High-palatable and caloric foods are widely overconsumed due to hedonic mechanisms that prevail over caloric necessities leading to overeating and overweight. The nucleus accumbens (NAc) is a key brain area modulating the reinforcing effects of palatable foods and is crucially involved in the development of eating disorders. We describe that prolonged exposure to high-caloric chocolate cafeteria diet leads to overeating and overweight in mice. NAc functionality was altered in these mice, presenting structural plasticity modifications in medium spiny neurons, increased expression of neuroinflammatory factors and activated microglia, and abnormal responses after amphetamine-induced hyperlocomotion. Chronic inactivation of microglia normalized these neurobiological and behavioural alterations exclusively in mice exposed to cafeteria diet. Our data suggest that prolonged exposure to cafeteria diet produces neuroplastic and functional changes in the NAc that can modify feeding behaviour. Microglia activation and neuroinflammation play an important role in the development of these neurobiological alterations.Frequency-specific power spectra maps were shown for healthy controls and alcoholics. Alcoholics exhibited aberrant frequency oscillation power across the whole frequency bandwidth. These frequency power aberrations were associated with cognitive functioning and may serve as a biomarker for identifying neural targets for repair.
      PubDate: 2017-09-05T02:30:57.604793-05:
      DOI: 10.1111/adb.12541
  • Levodopa prevents the reinstatement of cocaine self-administration in rats
           via potentiation of dopamine release in the medial prefrontal cortex
    • Authors: Silvia Antinori; Liana Fattore, Pierluigi Saba, Walter Fratta, Gian Luigi Gessa, Paola Devoto
      Pages: 556 - 568
      Abstract: Dopamine agonists have been proposed as therapeutic tools for cocaine addiction. We have recently demonstrated that indirect dopamine agonists, including levodopa (L-DOPA), markedly increase cocaine-induced dopamine release in the medial prefrontal cortex (mPFC) of rats leading to the suppression of cocaine-seeking behavior. This study was aimed to understand the behavioral and neurochemical effects of L-DOPA on cocaine-taking and cocaine-seeking in rats. After reaching a stable pattern of intravenous cocaine self-administration under a continuous fixed ratio (FR-1) schedule of reinforcement, male rats were treated with L-DOPA at different steps of the self-administration protocol. We found that L-DOPA reduced cocaine self-administration under FR-1 schedule of reinforcement and decreased the breaking points and the amount of cocaine self-administered under the progressive ratio schedule of reinforcement. Levodopa also decreased cocaine-seeking behavior both in a saline substitution test and in the cue priming-induced reinstatement test, without affecting general motor activity. Importantly, L-DOPA greatly potentiated cocaine-induced dopamine release in the mPFC of self-administering rats while reducing their cocaine intake. In the same brain area, L-DOPA also increased dopamine levels during cue priming-induced reinstatement of cocaine-seeking behavior. The potentiating effect was also evident in the mPFC but not nucleus accumbens core of drug-naïve rats passively administered with cocaine. Altogether, these findings demonstrate that L-DOPA efficaciously reduces the reinforcing and motivational effects of cocaine likely potentiating dopamine transmission in the mPFC. Its ability to prevent cue priming-induced reinstatement of cocaine-seeking suggests that it might be effective in reducing the risk to relapse to cocaine in abstinent patients.Systemic administration of levodopa (L-DOPA) potentiates cocaine-induced dopamine (DA) release in the rat medial prefrontal cortex (mPFC) during cocaine self-administration and contextually reduces cocaine-taking behavior. In the same brain area, after extinction of self-administration, L-DOPA administration increases DA levels and inhibits cocaine-seeking behavior during cue priming-induced reinstatement. Its ability to prevent cue priming-induced reinstatement of cocaine-seeking suggests that it might be effective in reducing the risk to relapse to cocaine in abstinent patients.
      PubDate: 2017-04-21T05:20:46.265804-05:
      DOI: 10.1111/adb.12509
  • Dopamine D1 or D2 receptor-expressing neurons in the central nervous
    • Authors: Xiaoyan Wei; Tengfei Ma, Yifeng Cheng, Cathy C.Y. Huang, Xuehua Wang, Jiayi Lu, Jun Wang
      Pages: 569 - 584
      Abstract: Dopamine signals mainly through D1 receptors (D1Rs) and D2 receptors (D2Rs); D1R-expressing or D2R-expressing neurons contribute to distinct reward and addictive behaviors. Traditionally, transgenic mice expressing green fluorescent protein (GFP) under D1R or D2R promoters are used for fluorescent verification in electrophysiology studies, whereas Cre mice are employed for behavioral research. However, it is unknown whether the same neuronal populations are targeted in GFP and Cre mice. Additionally, while D1Rs and D2Rs are known to be expressed in different striatal neurons, their expression patterns outside the striatum remain unclear. The present study addressed these two questions by using several transgenic mouse lines expressing fluorescent proteins (GFP or tdTomato) or Cre under the control of D1R or D2R promoters. We found a high degree of overlap between GFP-positive and Cre-positive neurons in the striatum and hippocampus. Additionally, we discovered that D1Rs and D2Rs were highly segregated in the orbitofrontal cortex, prefrontal cortex, dorsal and ventral hippocampus, and amygdala: ~4–34 percent of neurons co-expressed these receptors. Importantly, slice electrophysiological studies demonstrated that D1R-positive and D1R-negative hippocampal neurons were functionally distinct in a mouse line generated by crossing Drd1a-Cre mice with a Cre reporter Ai14 line. Lastly, we discovered that chronic alcohol intake differentially altered D1R-positive and D2R-positive neuron excitability in the ventral CA1. These data suggest that GFP and Cre mice target the same populations of striatal neurons, D1R-expressing or D2R-expressing neurons are highly segregated outside the striatum, and these neurons in the ventral hippocampal may exert distinct roles in alcohol addiction.D1(D2)-GFP and D1(D2)-Cre mice target the same populations of striatal neurons. D1R-expressing and D2R-expressing neurons are highly segregated in the cortex, hippocampus, and amygdala. Excessive alcohol consumption distinctly regulates excitability of D1R-expressing and D2R-expressing ventral CA1 neurons.
      PubDate: 2017-04-24T05:04:46.143109-05:
      DOI: 10.1111/adb.12512
  • Buprenorphine requires concomitant activation of NOP and MOP receptors to
           reduce cocaine consumption
    • Authors: Marsida Kallupi; Qianwei Shen, Giordano Guglielmo, Dennis Yasuda, V. Blair Journigan, Nurulain T. Zaveri, Roberto Ciccocioppo
      Pages: 585 - 595
      Abstract: Buprenorphine's clinical use is approved for the treatment of heroin addiction; however, evidence supporting its efficacy in cocaine abuse also exists. While for heroin it has been demonstrated that the effect of buprenorphine is mediated by its ability to activate μ-opioid peptide receptor (MOP) receptors, the mechanism through which it attenuates cocaine intake remains elusive. We explored this mechanism using operant models where rodents were trained to chronically self-administer cocaine for 2 hours daily. Buprenorphine (0.3, 1.0 and 3.0 mg/kg) given intraperitoneally 90 minutes before access to cocaine significantly and dose dependently reduced its intake. Pre-treatment with naltrexone or with the selective nociceptin/orphanin FQ peptide (NOP) antagonist SB-612111 did not prevent buprenorphine-induced reduction of cocaine intake. However, when naltrexone and SB-612111 were combined, the effect of buprenorphine on cocaine was completely prevented. To confirm that co-activation of MOP and NOP receptors is the underlying mechanism through which buprenorphine reduces cocaine intake, three compounds, namely, AT-034, AT-201 and AT-202, with a range of affinity and intrinsic activity profiles for MOP and NOP receptors, but weak ability for kappa-opioid peptide receptor (KOP) transmission, were tested. Consistent with our hypothesis based on buprenorphine's effects, results demonstrated that AT-034 and AT-201, which co-activate MOP and NOP receptors, reduced cocaine self-administration like buprenorphine. AT-202, which selectively stimulates NOP receptors, was not effective. Together, these data demonstrate that for buprenorphine, co-activation of MOP and NOP receptors is essential to reduce cocaine consumption. These results open new vistas on the treatment of cocaine addiction by developing compounds with mixed MOP/NOP agonist properties.Buprenorphine, at all doses tested, reduced significantly, in a dose-dependent manner, the number of cocaine rewards. However, treatment with the combination (SB-612111 30.0 mg + Nltx 2.5 mg) completely prevented the reduction of cocaine self-administration by buprenorphine.
      PubDate: 2017-06-21T01:14:08.285903-05:
      DOI: 10.1111/adb.12513
  • Noradrenergic signaling in the VTA modulates cocaine craving
    • Authors: Wojciech Barnaba Solecki; Klaudia Szklarczyk, Kamil Pradel, Krystyna Kwiatkowska, Grzegorz Dobrzański, Ryszard Przewłocki
      Pages: 596 - 609
      Abstract: Exposure to drug-associated cues evokes drug-seeking behavior and is regarded as a major cause of relapse. Conditional stimulus upregulates noradrenaline (NA) system activity, but the drug-seeking behavior depends particularly on phasic dopamine signaling downstream from the ventral tegmental area (VTA). The VTA dopamine-ergic activity is regulated via the signaling of alpha1-adrenergic and alpha2-adrenergic receptors (α1-ARs and α2-ARs); thus, the impact of the conditional stimulus on drug-seeking behavior might involve NAergic signaling in the VTA. To date, the role of VTA ARs in regulating cocaine seeking was not studied. We found that cocaine seeking under extinction conditions in male Sprague–Dawley rats was attenuated by intra-VTA prazosin or terazosin—two selective α1-AR antagonists. In contrast, cocaine seeking was facilitated by intra-VTA administration of the selective α1-AR agonist phenylephrine as well as α2-AR antagonist RX 821002, whereas the selective β-AR antagonist propranolol had no effects. In addition, blockade of α1-AR in the VTA prevented α2-AR antagonist-induced enhancement of cocaine seeking. Importantly, the potential non-specific effects of the VTA AR blockade on cocaine seeking could be excluded, because none of the AR antagonists influenced sucrose seeking under extinction conditions or locomotor activity in the open field test. These results demonstrate that NAergic signaling potently and selectively regulates cocaine seeking during early cocaine withdrawal via VTA α1-AR and α2-AR but not β-AR. Our findings provide new insight into the NAergic mechanisms that underlie cocaine craving.Cocaine seeking under extinctiong criteria in rats is attenuated by intra-ventral tegmental area (VTA) selective α1-AR antagonists (prazosin and terazois). In contrast, cocaine seeking is facilitated by intra-VTA administration of the selective α1-AR agonist (phenylephrine) as well as α2-AR antagonist (RX 821002), whereas the selective β-AR antagonist (propranolol) has no effects. Importantly, the potential nonspecific effects of the VTA AR blockade on cocaine seeking could be excluded, because none of the AR antagonists influenced sucrose seeking or locomotor activity.
      PubDate: 2017-06-21T03:51:39.323586-05:
      DOI: 10.1111/adb.12514
  • Intravenous self-administration of benzydamine, a non-steroidal
           anti-inflammatory drug with a central cannabinoidergic mechanism of action
    • Authors: Riccardo Avvisati; Maria Meringolo, Emiliana Stendardo, Elisa Malavasi, Silvia Marinelli, Aldo Badiani
      Pages: 610 - 619
      Abstract: Benzydamine (BZY) is a non-steroidal anti-inflammatory drug used for the topical treatment of inflammations of the oral and vaginal mucosae. Virtually nothing is known about the central pharmacological actions of BZY. Yet there are reports of voluntary systemic overdosage of BZY in drug addicts, resulting in a euphoric, hallucinatory state. In the present study, we investigated the reinforcing properties of BZY in a rat self-administration paradigm. We found that BZY has a powerful reinforcing effect and that this effect is greatly facilitated in animals that already had substance experience, having previously self-administered heroin and cocaine, indicating cross sensitization between BZY and other common drugs of abuse. We then assessed the effect of BZY on prelimbic cortex-to-nucleus accumbens glutamatergic transmission, using field recordings in rat parasagittal brain slices. BZY dose-dependently reduced both field excitatory post synaptic potential amplitude and paired pulse ratio, suggesting a presynaptic mechanism of action. Similarly to the in vivo paradigm, also the electrophysiological effects of BZY were potentiated in slices from animals that had undergone cocaine and heroin self-administration. Furthermore, BZY-induced Long Term Depression (LTD)-like responses in the prelimbic cortex-to-nucleus accumbens circuitry were significantly reduced in the presence of the CB1 receptor antagonist AM251. These findings provide firm evidence of the abuse liability of BZY and suggest a possible cannabinoidergic mechanism of action. Further research is needed in order to give insights into the molecular mechanism underlying BZY psychoactive and reinforcing effects, to better understand its abuse potential.Abuse of the anti-inflammatory drug benzydamine (BZY) has been reported, especially in drug addicts, but experimental evidence is lacking. We report here that BZY (1) has powerful reinforcing effects in the rat and these effects are facilitated by previous exposure to cocaine and heroin and (2) induces long-term depression of cortico-accumbens synaptic transmission, a phenomenon partially blocked by CB1 receptor antagonism. Our findings provide firm evidence of the addictive potential of BZY and suggest a cannabinoidergic mechanism of action.
      PubDate: 2017-04-21T05:05:34.721177-05:
      DOI: 10.1111/adb.12516
  • Nicotine self-administration reverses cognitive deficits in a rat model
           for schizophrenia
    • Authors: Uta Waterhouse; Katharine A. Brennan, Bart A. Ellenbroek
      Pages: 620 - 630
      Abstract: High comorbidity between schizophrenia and tobacco addiction has been well established. Explanatory theories include nicotine as a cognitive enhancer ameliorating symptoms of schizophrenia and underlying shared substrates increasing susceptibility to addiction in these individuals. To test these non-mutually exclusive theories, the maternal immune activation (MIA) model was utilized. To this end, pregnant Sprague Dawley rats were subcutaneously injected with a bacterial endotoxin, lipopolysaccharide (0.5 mg/kg), on gestation days 10 and 11. Selective attention and working memory in adult male offspring were subsequently assessed using the latent inhibition and delayed non-matching to sample paradigms both before and after nicotine or saline self-administration. MIA led to deficits in both latent inhibition and delayed non-matching to sample in male offspring. Further, these animals showed a small but significantly increased responding for nicotine during self-administration acquisition, although there was no difference in dose–response effect or in progressive ratio testing. However, nicotine, but not saline self-administration, significantly ameliorated the cognitive deficits induced by MIA. While the male offspring of mothers prenatally exposed to lipopolysaccharide was only slightly more sensitive to the reinforcing effects of nicotine, after self-administration, the MIA-induced cognitive deficits significantly improved. These data lend support for the self-medication hypothesis of schizophrenia.Prenatal lipopolysaccharide (LPS) induces cognitive deficits in male offspring. Prenatal LPS does not enhance reinforcing properties of nicotine. Nicotine reverses cognitive deficits induced by prenatal LPS treatment.
      PubDate: 2017-05-12T02:40:51.7157-05:00
      DOI: 10.1111/adb.12517
  • Temporally specific miRNA expression patterns in the dorsal and ventral
           striatum of addiction-prone rats
    • Authors: Rikki K. Quinn; Morgan H. James, Guy E. Hawkins, Amanda L. Brown, Andrew Heathcote, Doug W. Smith, Murray J. Cairns, Christopher V. Dayas
      Pages: 631 - 642
      Abstract: MicroRNAs (miRNAs) within the ventral and dorsal striatum have been shown to regulate addiction-relevant behaviours. However, it is unclear how cocaine experience alone can alter the expression of addiction-relevant miRNAs within striatal subregions. Further, it is not known whether differential expression of miRNAs in the striatum contributes to individual differences in addiction vulnerability. We first examined the effect of cocaine self-administration on the expression of miR-101b, miR-137, miR-212 and miR-132 in nucleus accumbens core and nucleus accumbens shell (NAcSh), as well as dorsomedial striatum and dorsolateral striatum (DLS). We then examined the expression of these same miRNAs in striatal subregions of animals identified as being ‘addiction-prone’, either immediately following self-administration training or following extinction and relapse testing. Cocaine self-administration was associated with changes in miRNA expression in a regionally discrete manner within the striatum, with the most marked changes occurring in the nucleus accumbens core. When we examined the miRNA profile of addiction-prone rats following self-administration, we observed increased levels of miR-212 in the dorsomedial striatum. After extinction and relapse testing, addiction-prone rats showed significant increases in the expression of miR-101b, miR-137, miR-212 and miR-132 in NAcSh, and miR-137 in the DLS. This study identifies temporally specific changes in miRNA expression consistent with the engagement of distinct striatal subregions across the course of the addiction cycle. Increased dysregulation of miRNA expression in NAcSh and DLS at late stages of the addiction cycle may underlie habitual drug seeking, and may therefore aid in the identification of targets designed to treat addiction.Bayesian model averaging (BMA) is a novel method to identify rats with a predisposition to addiction and relapse vulnerability using early behaviour traits. Using our BMA model, we have shown that addiction-prone rats show a distinct temporal profile in miRNA expression in the striatum compared to addiction-resistant rats. Here we show that key miRNA involved in synaptic plasticity processes, including miR-137, and those previously implicated in addiction behaviours, including miR-212, are dysregulated throughout the addiction cycle.
      PubDate: 2017-06-13T23:30:33.334271-05:
      DOI: 10.1111/adb.12520
  • Effect of N-acetylcysteine on motivation, seeking and relapse to ethanol
    • Authors: Sophie Lebourgeois; María Carmen González-Marín, Jerome Jeanblanc, Mickael Naassila, Catherine Vilpoux
      Pages: 643 - 652
      Abstract: Alcohol use disorder is a chronic and highly relapsing disorder, characterized by a loss of control over alcohol consumption and craving. Several studies suggest a key role of glutamate in this disorder. In recent years, the modulation of cystine/glutamate exchange via the xc− system has emerged as a new therapeutic alternative for reducing the excitatory glutamatergic transmission observed after ethanol self-administration in both rats and humans. The objective of this study was to determine whether a treatment with N-acetylcysteine (NAC), a cystine prodrug, could reduce ethanol self-administration, ethanol-seeking behavior and reacquisition of ethanol self-administration. Male Long Evans rats were trained to self-administer 20 percent ethanol in operant cages for several weeks. Once the consumption surpassed 1 g of ethanol/kg body weight/15 minutes, the effect of an acute intraperitoneal injection of NAC (0, 25, 50 or 100 mg/kg) 1 hour before the beginning of each test was evaluated on different aspects of the operant self-administration behavior. We demonstrated antimotivational properties of NAC (100 mg/kg), as ethanol-reinforced responding was reduced in a fixed ratio (−35 percent) and in a progressive ratio schedule (−81 percent). NAC also reduced ethanol-seeking behavior (−77 percent) evaluated as extinction responding in a single extinction session. NAC was able to reduce reacquisition in rats that were abstinent for 17 days, while NAC had no effect on ethanol relapse in rats previously exposed to six extinction sessions. Overall, our results demonstrate that NAC limits motivation, seeking behavior and reacquisition in rats, making it a potential new treatment for the maintenance of abstinence.We report here N-acetylcysteine (NAC) efficacy to reduce operant ethanol self-administration in rats during short-time session of 15 minutes. NAC also reduces seeking and reacquisition following protracted abstinence. Our results suggest for the first time that NAC is a potential new anticraving treatment for reduction of alcohol relapse.
      PubDate: 2017-05-30T07:16:11.483229-05:
      DOI: 10.1111/adb.12521
  • Novel role and regulation of HDAC4 in cocaine-related behaviors
    • Authors: Rachel D. Penrod; Maria B. Carreira, Makoto Taniguchi, Jaswinder Kumar, Stephanie A. Maddox, Christopher W. Cowan
      Pages: 653 - 664
      Abstract: Epigenetic mechanisms have been proposed to contribute to persistent aspects of addiction-related behaviors. One family of epigenetic molecules that may regulate maladaptive behavioral changes produced by cocaine use are the histone deacetylases (HDACs)—key regulators of chromatin and gene expression. In particular, the class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) respond to changes in neuronal activity by modulating their distribution between the nucleus and cytoplasm—a process controlled in large part by changes in phosphorylation of conserved residues. Cocaine triggers a transient nuclear accumulation of HDAC5 that functions to limit the development of cocaine reward behavior. However, the role and regulation of the close family member, HDAC4, in cocaine behaviors remain largely unknown. In this study, we report that cocaine and cAMP signaling in striatum produced differential phosphorylation and subcellular localization of HDAC4 and HDAC5. Unlike HDAC5, cocaine exposure induced a modest hyperphosphorylation and nuclear export of HDAC4. Genetic deletion of HDAC4 in the nucleus accumbens reduced acute cocaine-produced locomotion, maximum locomotor sensitization and cocaine reward-related behavior. Interestingly, overexpression of an HDAC4 cytoplasm-concentrated mutant (S266E) increased cocaine reward behavior in the cocaine conditioned place preference assay, suggesting that cocaine-induced nuclear export of HDAC4 might function to facilitate the development of cocaine reward behaviors through a role in the cell cytoplasm. Together, our findings suggest that, despite high sequence homology, HDAC4 and HDAC5 are oppositely regulated by cocaine-induced signaling in vivo and have distinct roles in regulating cocaine behaviors.In the nucleus accumbens, HDAC4 is hyperphosphorylated and re-localized to the cytoplasm in response to cocaine. Loss of neuronal HDAC4 in the adult mouse nucleus accumbens reduces behavioral responses to cocaine. Overexpression of a phospho-mimetic mutant of HDAC4 enhances cocaine reward behavior, suggesting a possible cytoplasmic role in addiction-related behaviors.
      PubDate: 2017-06-21T03:22:07.306139-05:
      DOI: 10.1111/adb.12522
  • Dentate gyrus neurogenesis ablation via cranial irradiation enhances
           morphine self-administration and locomotor sensitization
    • Authors: Sarah E. Bulin; Matthew L. Mendoza, Devon R. Richardson, Kwang H. Song, Timothy D. Solberg, Sanghee Yun, Amelia J. Eisch
      Pages: 665 - 675
      Abstract: Adult dentate gyrus (DG) neurogenesis is important for hippocampal-dependent learning and memory, but the role of new neurons in addiction-relevant learning and memory is unclear. To test the hypothesis that neurogenesis is involved in the vulnerability to morphine addiction, we ablated adult DG neurogenesis and examined morphine self-administration (MSA) and locomotor sensitization. Male Sprague–Dawley rats underwent hippocampal-focused, image-guided X-ray irradiation (IRR) to eliminate new DG neurons or sham treatment (Sham). Six weeks later, rats underwent either MSA (Sham = 16, IRR = 15) or locomotor sensitization (Sham = 12, IRR = 12). Over 21 days of MSA, IRR rats self-administered ~70 percent more morphine than Sham rats. After 28 days of withdrawal, IRR rats pressed the active lever 40 percent more than Sham during extinction. This was not a general enhancement of learning or locomotion, as IRR and Sham groups had similar operant learning and inactive lever presses. For locomotor sensitization, both IRR and Sham rats sensitized, but IRR rats sensitized faster and to a greater extent. Furthermore, dose–response revealed that IRR rats were more sensitive at a lower dose. Importantly, these increases in locomotor activity were not apparent after acute morphine administration and were not a byproduct of irradiation or post-irradiation recovery time. Therefore, these data, along with other previously published data, indicate that reduced hippocampal neurogenesis confers vulnerability for multiple classes of drugs. Thus, therapeutics to specifically increase or stabilize hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.Rats underwent hippocampal-focused, image-guided X-ray irradiation to eliminate new dentate gyrus neurons or received a control treatment. Irradiated rats self-administered ˜70% more morphine than control rats, and pressed the active lever ˜40% more than control rats during extinction. Irradiated rats also sensitized faster and to a greater extent than control rats in locomotor sensitization.
      PubDate: 2017-06-19T03:55:58.774177-05:
      DOI: 10.1111/adb.12524
  • CB1 and ethanol effects on glutamatergic transmission in the central
           amygdala of male and female msP and Wistar rats
    • Authors: Dean Kirson; Christopher Shaun Oleata, Loren Howell Parsons, Roberto Ciccocioppo, Marisa Roberto
      Pages: 676 - 688
      Abstract: The central amygdala (CeA) is involved in the processing of anxiety and stress and plays a role in ethanol consumption. Chronic ethanol recruits stress systems in the CeA, leading to aversive withdrawal symptoms. Although primarily GABAergic, CeA contains glutamatergic afferents, and we have reported inhibitory effects of ethanol on locally evoked glutamatergic responses in CeA of Wistar and Marchigian Sardinian alcohol-preferring (msP) rats. Notably, msP rats display enhanced anxiety, stress and alcohol drinking, simulating the alcohol-dependent phenotype. Endocannabinoids are also involved in regulation of stress, and we previously demonstrated that cannabinoid receptor type 1 (CB1) activation decreases CeA GABAergic signaling and blocks ethanol enhancement of GABAergic signaling. Here, we sought to investigate the effects of CB1 activation (WIN 55,212–2; Win) and antagonism (AM251) with and without acute ethanol on glutamatergic synapses in CeA of female and male Wistar and msP rats. Using intracellular sharp pipette electrophysiology, we examined the effects of CB1 compounds on locally evoked excitatory postsynaptic potentials (EPSPs) in CeA and compared effects between strains, gender and estrous cycle. Acute ethanol decreased EPSP amplitudes in Wistars, and in male but not female msPs. Win decreased EPSP amplitudes in msPs, and in male but not female Wistars. Combined application of Win and ethanol resulted in strain-specific effects in female rats. We found no tonic CB1 signaling at glutamatergic synapses in CeA of any groups, and no interaction with ethanol. Collectively, these observations demonstrate sex–strain-specific differences in ethanol and endocannabinoid effects on CeA glutamatergic signaling.The Marchigian Sardinian alcohol-preferring (msP) rat simulates the high-stress alcohol-dependent phenotype. We examined cannabinoid receptor type 1 (CB1)-mediated effects on evoked glutamatergic signaling in the central amygdala (CeA), and interactions with acute ethanol, in male and female msP and Wistar rats. We found strain-dependent/sex-dependent inhibition of excitatory postsynaptic potentials with ethanol and CB1 agonism and strain-specific effects of the combined drugs in female rats. These observations demonstrate sex differences in response to the intersection of stress and alcohol.
      PubDate: 2017-06-28T02:31:49.174303-05:
      DOI: 10.1111/adb.12525
  • Long-term subregion-specific encoding of enhanced ethanol intake by D1DR
           medium spiny neurons of the nucleus accumbens
    • Authors: Rafael Renteria; Tavanna R. Buske, Richard A. Morrisett
      Pages: 689 - 698
      Abstract: The nucleus accumbens (NAc) is a critical component of the mesocorticolimbic system and is involved in mediating the motivational and reinforcing aspects of ethanol consumption. Chronic intermittent ethanol (CIE) exposure is a reliable model to induce ethanol dependence and increase volitional ethanol consumption in mice. Following a CIE-induced escalation of ethanol consumption, NMDAR (N-methyl-D-aspartate receptor)-dependent long-term depression in D1 dopamine receptor expressing medium spiny neurons of the NAc shell was markedly altered with no changes in plasticity in D1 dopamine receptor medium spiny neurons from the NAc core. This disruption of plasticity persisted for up to 2 weeks after cessation of ethanol access. To determine if changes in AMPA receptor (AMPAR) composition contribute to this ethanol-induced neuroadaptation, we monitored the rectification of AMPAR excitatory postsynaptic currents (EPSCs). We observed a marked decrease in the rectification index in the NAc shell, suggesting the presence of GluA2-lacking AMPARs. There was no change in the amplitude of spontaneous EPSCs (sEPSCs), but there was a transient increase in sEPSC frequency in the NAc shell. Using the paired pulse ratio, we detected a similar transient increase in the probability of neurotransmitter release. With no change in sEPSC amplitude, the change in the rectification index suggests that GluA2-containing AMPARs are removed and replaced with GluA2-lacking AMPARs in the NAc shell. This CIE-induced alteration in AMPAR subunit composition may contribute to the loss of NMDAR-dependent long-term depression in the NAc shell and therefore may constitute a critical neuroadaptive response underlying the escalation of ethanol intake in the CIE model.Using a model of alcohol dependence, chronic intermittent ethanol (CIE), we observed a long-term disruption in the expression of NMDAR-dependent plasticity and a change in the rectification index of AMPA receptor mediated currents in D1 medium spiny neurons (MSNs) of the NAc shell but not the NAc core. These changes in plasticity and excitatory signaling in D1 MSNs of the NAc shell may constitute a critical neuroadaptive response underlying the escalation of ethanol intake in the CIE model.
      PubDate: 2017-06-28T01:40:28.187403-05:
      DOI: 10.1111/adb.12526
  • A new generation of mTORC1 inhibitor attenuates alcohol intake and reward
           in mice
    • Authors: Nadege Morisot; Christopher J. Novotny, Kevan M. Shokat, Dorit Ron
      Pages: 713 - 722
      Abstract: Alcohol use disorder (AUD) is a chronic condition associated with devastating socioeconomic consequences. Yet, pharmacotherapies to treat behavioral phenotypes such as uncontrolled heavy drinking are limited. Studies in rodents suggest that the mammalian target of rapamycin complex 1 (mTORC1) plays an important role in mechanisms underlying alcohol drinking behaviors as well as alcohol seeking and relapse. These preclinical evidence suggest that mTORC1 may be a therapeutic target for the treatment of AUD. Thus, the aim of the present study was to test the potential use of newly developed mTORC1 inhibitors, RapaLink-1 and MLN0128, in preclinical mouse models of AUD. First, we used the intermittent access to 20 percent alcohol in a two-bottle choice paradigm and tested the efficacy of the drugs to reduce alcohol intake in mice with a history of binge drinking and withdrawal. We found that both inhibitors reduce excessive alcohol intake and preference with RapaLink-1 exhibiting higher efficacy. We further observed that RapaLink-1 attenuates alcohol consumption during the first alcohol-drinking session in naïve mice, and interestingly, the effect was still present 14 days after the initial treatment with the drug. We also found that RapaLink-1 did not alter the consumption of water or saccharin, revealing a specific effect of the inhibitor on alcohol intake. Finally, we report that RapaLink-1 blocks the retrieval but not acquisition of alcohol place preference without affecting locomotion. Together, our findings suggest that RapaLink-1 may be developed as a new medication to treat and prevent the development of AUD.Mammalian target of rapamycin complex 1 (mTORC1) contributes to mechanisms underlying excessive alcohol consumption. In this manuscript, Morisot et al. examined the efficacy of new classes of mTORC1 inhibitors to attenuate alcohol-dependent behaviors in mice. The authors found that systemic administration of the mTORC1 inhibitor, Rapalink-1, inhibits alcohol intake and reward and produces a long-lasting inhibition when administered prior to the first binge drinking session. Together, the findings suggest that mTORC1 inhibitors may be developed for the treatment of alcohol use disorder.
      PubDate: 2017-07-06T00:00:54.288169-05:
      DOI: 10.1111/adb.12528
  • Fatty acid amide hydrolase (FAAH) inactivation confers enhanced
           sensitivity to nicotine-induced dopamine release in the mouse nucleus
    • Authors: Francisco J. Pavon; Antonia Serrano, Nimish Sidhpura, Ilham Polis, David Stouffer, Fernando Rodriguez Fonseca, Benjamin F. Cravatt, Rémi Martin-Fardon, Loren H. Parsons
      Pages: 723 - 734
      Abstract: Nicotine exerts its rewarding effects by promoting an increase in dopamine (DA) release in the nucleus accumbens (NAc), and this process is influenced by the endocannabinoid system. Fatty acid amide hydrolase (FAAH) is the main enzyme responsible for the degradation of the endocannabinoid anandamide and other non-cannabinoid N-acylethanolamines. Previous research has reported that both genetic deletion and pharmacological inhibition of FAAH enhance nicotine-induced conditioned place preference at low doses. We conducted a microdialysis study to characterize nicotine-induced changes in DA and serotonin (5-HT) levels in the NAc of FAAH knockout (KO) mice using a conditioned place preference-like paradigm with three nicotine doses (0.1, 1 and 10 mg/kg, s.c.). Additionally, the effects of the selective FAAH inhibitor PF-3845 (10 mg/kg, i.p.) were also examined. Our data indicated that compared with wild-type mice, genetic deletion of FAAH selectively enhanced the effect of low-dose nicotine on DA release (p 
      PubDate: 2017-06-29T03:55:38.59115-05:0
      DOI: 10.1111/adb.12531
  • Effects of sleep on substance use in adolescents: a longitudinal
    • Authors: Tam T. Nguyen-Louie; Ty Brumback, Matthew J. Worley, Ian M. Colrain, Georg E. Matt, Lindsay M. Squeglia, Susan F. Tapert
      Pages: 750 - 760
      Abstract: Substance use (SU) and sleep problems appear interrelated, but few studies have examined the influence of adolescent sleep patterns on development of SU disorders. This study prospectively examined the influence of sleep habits on subsequent SU in youth who later transitioned into heavy drinking. At time 1 (T1), participants (n = 95) were substance-naive 12- to 14-year-olds. Path-analytic models examined whether the effects of T1 risk factors (familial SU disorder, inhibition control, and externalizing and internalizing traits) on time 3 (M = 19.8 years old) tobacco, alcohol, and cannabis were mediated by time 2 (M = 15.1 years old) sleep chronotype, daytime sleepiness, and erratic sleep/wake behaviors. Significant direct path effects of T1 risk factors and time 2 sleep behaviors on time 3 SU were found, Ps 
      PubDate: 2017-05-26T01:51:01.799676-05:
      DOI: 10.1111/adb.12519
  • Adolescents' behavioral and neural responses to e-cigarette advertising
    • Authors: Yvonnes Chen; Carina H. Fowler, Vlad B. Papa, Rebecca J. Lepping, Morgan G. Brucks, Andrew T. Fox, Laura E. Martin
      Pages: 761 - 771
      Abstract: Although adolescents are a group heavily targeted by the e-cigarette industry, research in cue-reactivity has not previously examined adolescents' behavioral and neural responses to e-cigarette advertising. This study addressed this gap through two experiments. In Experiment One, adult traditional cigarette smokers (n = 41) and non-smokers (n = 41) answered questions about e-cigarette and neutral advertising images. The 40 e-cigarette advertising images that most increased desire to use the product were matched to 40 neutral advertising images with similar content. In Experiment Two, the 80 advertising images selected in Experiment One were presented to adolescents (n = 30) during an functional magnetic resonance imaging brain scan. There was a range of traditional cigarette smoking across the sample with some adolescents engaging in daily smoking and others who had never smoked. Adolescents self-reported that viewing the e-cigarette advertising images increased their desire to smoke. Additionally, all participants regardless of smoking statuses showed significantly greater brain activation to e-cigarette advertisements in areas associated with cognitive control (left middle frontal gyrus), reward (right medial frontal gyrus), visual processing/attention (left lingual gyrus/fusiform gyrus, right inferior parietal lobule, left posterior cingulate, left angular gyrus) and memory (right parahippocampus, left insula). Further, an exploratory analysis showed that compared with age-matched non-smokers (n = 7), adolescent smokers (n = 7) displayed significantly greater neural activation to e-cigarette advertising images in the left inferior temporal gyrus/fusiform gyrus, compared with their responses to neutral advertising images. Overall, participants' brain responses to e-cigarette advertisements suggest a need to further investigate the long-run impact of e-cigarette advertising on adolescents.Adolescents (n = 30) with various smoking experiences (non-smokers to daily smokers) self-reported that viewing the e-cigarette advertisements increased their desire to smoke. They also showed significantly greater brain activation to e-cigarette advertisements in areas associated with cognitive control, reward, visual processing/attention, and memory. Further, an exploratory analysis showed that compared to age-matched non-smokers (n = 7), adolescent smokers (n = 7) displayed significantly greater neural activation to e-cigarette advertising images in the left inferior temporal gyrus/fusiform gyrus, compared to their responses to neutral advertising images.
      PubDate: 2017-04-11T23:20:35.911987-05:
      DOI: 10.1111/adb.12510
  • Altered interhemispheric resting-state functional connectivity in young
           male smokers
    • Authors: Dahua Yu; Kai Yuan, Yanzhi Bi, Lin Luo, Jinquan Zhai, Bo Liu, Yangding Li, Jiadong Cheng, Yanyan Guan, Ting Xue, Limei Bu, Shaoping Su, Yao Ma, Wei Qin, Jie Tian, Xiaoqi Lu
      Pages: 772 - 780
      Abstract: With the help of advanced neuroimaging approaches, previous studies revealed structural and functional brain changes in smokers compared with healthy non-smokers. Homotopic resting-state functional connectivity between the corresponding regions in cerebral hemispheres may help us to deduce the changes of functional coordination in the whole brain of young male smokers. Functional homotopy reflects an essential aspect of brain function and communication between the left and right cerebral hemispheres, which is important for the integrity of brain function. However, few studies used voxel mirrored homotopic connectivity (VMHC) method to investigate the changes of homotopic connectivity in young male smokers. Twenty-seven young male smokers and 27 matched healthy male non-smokers were recruited in our study. Compared with healthy male non-smokers, young male smokers showed decreased VMHC values in the insula and putamen, and increased VMHC values in the prefrontal cortex. Correlation analysis demonstrated that there were significant positive correlations between the average VMHC values of the prefrontal cortex and pack-years in young male smokers. In addition, significant negative correlation was found between the average VMHC values in the insula and pack-years. Our results revealed the disrupted homotopic resting-state functional connectivity in young male smokers. The novel findings may extend our understanding of smoking.Compared with healthy male non-smokers, young male smokers showed decreased voxel mirrored homotopic voxel (VMHC) values in the insula and putamen, and increased VMHC values in the prefrontal cortex. Correlation analysis demonstrated that there were significant correlations between pack-years and the average VMHC values of the prefrontal cortex and insula. Our results revealed the disrupted homotopic resting-state functional connectivity in young male smokers, which may extend our understanding of smoking.
      PubDate: 2017-05-05T04:34:40.256403-05:
      DOI: 10.1111/adb.12515
  • Regional cerebral blood flow in opiate dependence relates to substance use
           and neuropsychological performance
    • Authors: Donna E. Murray; Timothy C. Durazzo, Thomas P. Schmidt, Troy A. Murray, Christoph Abé, Joseph Guydish, Dieter J. Meyerhoff
      Pages: 781 - 795
      Abstract: Neuroimaging of opiate-dependent individuals indicates both altered brain structure and function. Magnetic resonance-based arterial spin labeling has been used to measure noninvasively cerebral blood flow (i.e. perfusion) in alcohol, tobacco and stimulant dependence; only one arterial spin labeling paper in opiate-dependent individuals demonstrated frontal and parietal perfusion deficits. Additional research on regional brain perfusion in opiate dependence and its relationship to cognition and self-regulation (impulsivity, risk taking and decision making) may inform treatment approaches for opiate-dependent individuals. Continuous arterial spin labeling magnetic resonance imaging at 4 T and neuropsychological measures assessed absolute brain perfusion levels, cognition and self-regulation in 18 cigarette smoking opiate-dependent individuals (sODI) stable on buprenorphine maintenance therapy. The sODI were compared with 20 abstinent smoking alcohol-dependent individuals (a substance-dependent control group), 35 smoking controls and 29 nonsmoking controls. sODI had lower perfusion in several cortical and subcortical regions including regions within the brain reward/executive oversight system compared with smoking alcohol-dependent individuals and nonsmoking controls. Perfusion was increased in anterior cingulate cortex and globus pallidus of sODI. Compared with all other groups, sODI had greater age-related declines in perfusion in most brain reward/executive oversight system and some other regions. In sODI, lower regional perfusion related to greater substance use, higher impulsivity and weaker visuospatial skills. Overall, sODI showed cortical and subcortical hypoperfusion and hyperperfusion. Relating to neuropsychological performance and substance use quantities, the frontal perfusion alterations are clinically relevant and constitute potential targets for pharmacological and cognitive-based therapeutic interventions to improve treatment outcome in opiate dependence.Regional brain perfusion in opiate dependent individuals (sODI) was measured with arterial spin labeling magnetic resonance imaging. Perfusion was increased in anterior cingulate cortex and globus pallidus of sODI. sODI had greater age-related declines in perfusion in most brain reward/executive oversight system regions than control groups (smokers and non-smokers) and a substance-dependent control group. In sODI, lower regional perfusion was related to greater substance use, higher impulsivity, and weaker visuospatial skills. Overall, sODI showed cortical and subcortical hypo-perfusion and hyperperfusion.
      PubDate: 2017-06-19T04:45:53.97421-05:0
      DOI: 10.1111/adb.12523
  • Cocaine and HIV are independently associated with neural activation in
           response to gain and loss valuation during economic risky choice
    • Authors: Christina S. Meade; Merideth Addicott, Andrea L. Hobkirk, Sheri L. Towe, Nan-Kuei Chen, Sriramkumar Sridharan, Scott A. Huettel
      Pages: 796 - 809
      Abstract: Stimulant abuse is disproportionately common in HIV-positive persons. Both HIV and stimulants are independently associated with deficits in reward-based decision making, but their interactive and/or additive effects are poorly understood despite their prevalent co-morbidity. Here, we examined the effects of cocaine dependence and HIV infection in 69 adults who underwent functional magnetic resonance imaging while completing an economic loss aversion task. We identified two neural networks that correlated with the evaluation of the favorable characteristics of the gamble (i.e. higher gains/lower losses: ventromedial prefrontal cortex, anterior cingulate, anterior and posterior precuneus and visual cortex) versus unfavorable characteristics of the gamble (i.e. lower gains/higher losses: dorsal prefrontal, lateral orbitofrontal, posterior parietal cortex, anterior insula and dorsal caudate). Behaviorally, cocaine and HIV had additive effects on loss aversion scores, with HIV-positive cocaine users being the least loss averse. Cocaine users had greater activation in brain regions that tracked the favorability of gamble characteristics (i.e. increased activation to gains, but decreased activation to losses). In contrast, HIV infection was independently associated with lesser activation in regions that tracked the unfavorability of gamble characteristics. These results suggest that cocaine is associated with an overactive reward-seeking system, while HIV is associated with an underactive cognitive control system. Together, these alterations may leave HIV-positive cocaine users particularly vulnerable to making unfavorable decisions when outcomes are uncertain.We examined the effects of cocaine dependence and HIV infection in 69 adults who underwent functional magnetic resonance imaging while completing an economic risk task. Cocaine was associated with greater activation in response to increasing favorability of gambles (i.e., higher gains/lower losses) in reward-related regions (e.g., ACC and VMPFC), while HIV was associated with less activation in response to increasing unfavorability of gambles (i.e., lower gains/higher losses) in cognitive control regions (e.g., DLPFC and PPC).
      PubDate: 2017-07-06T05:18:28.364131-05:
      DOI: 10.1111/adb.12529
  • Adolescent alcohol exposure decreases frontostriatal resting-state
           functional connectivity in adulthood
    • Authors: Margaret A. Broadwater; Sung-Ho Lee, Yang Yu, Hongtu Zhu, Fulton T. Crews, Donita L. Robinson, Yen-Yu Ian Shih
      Pages: 810 - 823
      Abstract: Connectivity of the prefrontal cortex (PFC) matures through adolescence, coinciding with emergence of adult executive function and top-down inhibitory control over behavior. Alcohol exposure during this critical period of brain maturation may affect development of PFC and frontolimbic connectivity. Adult rats exposed to adolescent intermittent ethanol (AIE; 5 g/kg ethanol, 25 percent v/v in water, intragastrically, 2-day-on, 2-day-off, postnatal day 25–54) or water control underwent resting-state functional MRI to test the hypothesis that AIE induces persistent changes in frontolimbic functional connectivity under baseline and acute alcohol conditions (2 g/kg ethanol or saline, intraperitoneally administered during scanning). Data were acquired on a Bruker 9.4-T MR scanner with rats under dexmedetomidine sedation in combination with isoflurane. Frontolimbic network regions-of-interest for data analysis included PFC [prelimbic (PrL), infralimbic (IL), and orbitofrontal cortex (OFC) portions], nucleus accumbens (NAc), caudate putamen (CPu), dorsal hippocampus, ventral tegmental area, amygdala, and somatosensory forelimb used as a control region. AIE decreased baseline resting-state connectivity between PFC subregions (PrL-IL and IL-OFC) and between PFC-striatal regions (PrL-NAc, IL-CPu, IL-NAc, OFC-CPu, and OFC-NAc). Acute ethanol induced negative blood-oxygen-level-dependent changes within all regions of interest examined, along with significant increases in functional connectivity in control, but not AIE animals. Together, these data support the hypothesis that binge-like adolescent alcohol exposure causes persistent decreases in baseline frontolimbic (particularly frontostriatal) connectivity and alters sensitivity to acute ethanol-induced increases in functional connectivity in adulthood.Adolescent intermittent ethanol decreased baseline resting-state connectivity between prefrontal cortex subregions (PrL-IL and IL-OFC) and between prefrontal cortex-striatal regions (PrL-NAc, IL-CPu, IL-NAc, OFC-CPu and OFC-NAc). Acute ethanol induced negative BOLD changes within all ROIs examined, along with significant increases in functional connectivity in control, but not adolescent intermittent ethanol animals. Together these data support the hypothesis that binge-like adolescent alcohol exposure causes persistent decreases in frontostriatal connectivity and alters sensitivity to acute ethanol-induced increases in functional connectivity in adulthood.
      PubDate: 2017-07-09T22:40:56.1361-05:00
      DOI: 10.1111/adb.12530
  • Aberrant blood-oxygen-level-dependent signal oscillations across frequency
           bands characterize the alcoholic brain
    • Authors: Jui-Yang Hong; Eva M. Müller-Oehring, Adolf Pfefferbaum, Edith V. Sullivan, Dongjin Kwon, Tilman Schulte
      Pages: 824 - 835
      Abstract: Chronic alcoholism is associated with widespread regional differences from controls in brain activity and connectivity dynamics measured by blood-oxygen-level-dependent (BOLD) signals. Identification of alcoholism-related neurofunctional power dynamics using functional magnetic resonance imaging (fMRI) that relate to cognition and behavior may serve as biomarkers of alcoholism. Previously, resting-state fMRI studies examined BOLD signals at a single low-frequency (LF) bandwidth. BOLD signals, however, oscillate systematically at different frequencies and are organized in a resting brain where LF oscillation facilitates long-distance communication between regions across cortical regions, whereas high-frequency (HF) oscillation occurs in closely localized, subcortical areas. Using a frequency power quantification approach, we investigated whether the organization of BOLD signal oscillations across all measured frequency bandwidths is altered in alcoholism and relates to cognitive performance. Frequency-dependent oscillation power differences between 56 sober alcoholics and 56 healthy controls occurred for all frequency bands. Alcoholics exhibited greater frequency oscillation power in the orbitofrontal cortex and less power in the posterior insula within the HF bandwidth than controls. Aberrant orbitofrontal HF power was associated with poorer memory performance and slower psychomotor speed in alcoholics. Middle-frequency and LF power proved sensitive in detecting altered frequency oscillation dynamics in parietal and postcentral cortical regions of alcoholics. This study is novel in identifying alcohol-related differences in BOLD oscillation power of the full fMRI frequency bandwidth. Specifically, HF power aberrations were associated with poorer cognitive functioning in alcoholism and may serve as a biomarker for identifying neural targets for repair.Frequency-specific power spectra maps were shown for healthy controls and alcoholics. Alcoholics exhibited aberrant frequency oscillation power across the whole frequency bandwidth. These frequency power aberrations were associated with cognitive functioning and may serve as a biomarker for identifying neural targets for repair.
      PubDate: 2017-07-12T06:25:32.31255-05:0
      DOI: 10.1111/adb.12532
  • A paradigm for examining stress effects on alcohol-motivated behaviors in
           participants with alcohol use disorder
    • Authors: Mary E. McCaul; Gary S. Wand, Elise M. Weerts, Xiaoqiang Xu
      Pages: 836 - 845
      Abstract: Although epidemiological research has shown an increase in drinking following stressors and trauma, limited paradigms have been validated to study the relationship between stress and drinking in the human laboratory. The current study developed a progressive ratio (PR) operant procedure to examine the effects of psychosocial stress on alcohol craving and several alcohol-motivated behaviors in persons with alcohol use disorder. Current heavy, nontreatment-seeking drinkers (N = 30) were media-recruited and completed a comprehensive assessment of recent drinking, mood and health. Participants were admitted to the clinical research unit and underwent 4-day, physician-monitored alcohol abstinence. On days 4 and 5, participants underwent the Trier Social Stress Test or a neutral session in random order followed by the alcohol-motivated response (AMR) procedure in which subjects worked for money or alcohol under a PR operant procedure. Subjects received earned money vouchers or alcohol at the conclusion of the session. The Trier Social Stress Test increased alcohol craving and rate of responding and decreased the number of changeovers between alcohol versus money reinforcers on the PR schedule. There was a positive relationship between alcohol craving and drinks earned during the stress session. This novel paradigm provides an experimental platform to examine motivation to drink without confounding by actual alcohol ingestion during the work session, thereby setting the stage for future studies of alcohol interventions.This study developed an alcohol-motivated response (AMR) procedure to examine effects of psychosocial stress on alcohol craving and several operant behaviors in persons with alcohol use disorder. Following the Trier Psychosocial Stress Test, there was a positive relationship between alcohol craving and drinks earned during the AMR session. This novel paradigm provides an experimental platform to examine motivation to drink without confounding by actual alcohol ingestion during the work session, setting the stage for future studies of alcohol interventions.
      PubDate: 2017-04-17T01:20:57.990613-05:
      DOI: 10.1111/adb.12511
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