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Publisher: John Wiley and Sons   (Total: 1589 journals)

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Showing 1 - 200 of 1589 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 12, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 65, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 47, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 52, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 164, 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: 15, SJR: 1.197, h-index: 81)
Acta Ophthalmologica     Hybrid Journal   (Followers: 6, 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: 35, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 7, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 4)
Addiction     Hybrid Journal   (Followers: 35, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 14, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 27, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 26, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 51, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 14, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 267, 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)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 17, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 13, 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: 10)
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: 15, 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: 33, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 51, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 148, 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: 92, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 29, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 34, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 12, 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: 16, 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: 37, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 278, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 3, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 17, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 138, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 9, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 18)
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: 219)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 222, 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 Human Genetics     Hybrid Journal   (Followers: 9, SJR: 1.191, h-index: 67)
Annals of Neurology     Hybrid Journal   (Followers: 47, 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: 13)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 25, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 17, 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: 89, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 49, 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: 70, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 207, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 49, 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: 14, 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: 11, 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: 27, 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: 25, 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: 12, SJR: 0.938, h-index: 57)
Art History     Hybrid Journal   (Followers: 246, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 52, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 27, 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: 16)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 320, 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   (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: 5, 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: 2, 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: 47, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 11, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 7, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 5, 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: 14, 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: 408, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 5, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 72, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 12, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 21, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 36, 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: 9, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 24, 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: 16, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 4, 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: 6, 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: 141, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 14, 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: 6, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)
BJOG : An Intl. J. of Obstetrics and Gynaecology     Partially Free   (Followers: 243, SJR: 2.083, h-index: 125)

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Journal Cover Addiction Biology
  [SJR: 2.091]   [H-I: 57]   [14 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  [1589 journals]
  • 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
  • Phosphorylated SNAP25 in the CA1 regulates morphine-associated contextual
           memory retrieval via increasing GluN2B-NMDAR surface localization
    • Authors: Xinjuan Wang; Yan Liu, Meng Jia, Xiaowei Sun, Na Wang, Yijing Li, Cailian Cui
      Abstract: Although our previous studies have demonstrated both protein kinase C (PKC) and GluN2B-containing N-methyl-d-aspartate receptor (GluN2B-NMDAR) play crucial roles in morphine-associated learning and memory, the relationship between them remains unexplored. In this study, we validated the enhanced PKC and membrane GluN2B protein expression in the hippocampal CA1 after morphine conditioned place preference (CPP) expression in rats. Interestingly, we also found that phosphorylation of SNAP25 at Ser187 (pSer187-SNAP25), a PKC-activated target, was significantly increased following morphine CPP expression. Blocking the pSer187-SNAP25 by intra-CA1 injection of an interfering peptide impaired morphine CPP expression and accompanied by the reduced ratio of GluN2B membrane/total in the CA1. In addition, intra-CA1 blockade of pSer187-SNAP25 did not affect natural learning and memory process as evidenced by intact sucrose-induced CPP expression and normal locomotor activity in rats. Therefore, our results reveal that enhanced pSer187-SNAP25 by PKC recruits GluN2B-NMDAR to the membrane surface in the hippocampal CA1 and mediates context-induced addiction memory retrieval. Our findings in this study fill in the missing link and provide better understanding of the molecular mechanisms involved in morphine-associated contextual memory retrieval.Protein kinase C (PKC), pSer187-SNAP25 and GluN2B was critical to morphine conditioned place preference (CPP) expression in the CA1.TAT-S187 peptide in the CA1 impaired morphine CPP expression and decreased the GluN2B surface localization.PKC interacted with pS187-SNAP25 accompanied by increasing GluN2B surface localization in the CA1 after morphine CPP expression.
      PubDate: 2017-09-08T06:16:07.623565-05:
      DOI: 10.1111/adb.12558
  • Cerebral dopaminergic and glutamatergic transmission relate to different
           subjective responses of acute alcohol intake: an in vivo multimodal
           imaging study
    • Authors: Gil Leurquin-Sterk; Jenny Ceccarini, Cleo Lina Crunelle, Akila Weerasekera, Bart Laat, Uwe Himmelreich, Guy Bormans, Koen Van Laere
      Abstract: Converging preclinical evidence links extrastriatal dopamine release and glutamatergic transmission via the metabotropic glutamate receptor 5 (mGluR5) to the rewarding properties of alcohol. To date, human evidence is lacking on how and where in the brain these processes occur. Mesocorticolimbic dopamine release upon intravenous alcohol administration and mGluR5 availability were measured in 11 moderate social drinkers by single-session [18F]fallypride and [18F]FPEB positron emission tomography, respectively. Additionally, baseline and postalcohol glutamate and glutamine levels in the anterior cingulate cortex (ACC) were measured by using proton-magnetic resonance spectroscopy. To investigate differences in reward domains linked to both neurotransmitters, regional imaging data were related to subjective alcohol responses. Alcohol induced significant [18F]fallypride displacement in the prefrontal cortex (PFC), temporal and parietal cortices and thalamus (P 
      PubDate: 2017-09-08T06:06:55.946909-05:
      DOI: 10.1111/adb.12542
  • Self-efficacy modulates the neural correlates of craving in male smokers
           and ex-smokers: an fMRI study
    • Authors: Miki Ono; Takanori Kochiyama, Junya Fujino, Takashi Sozu, Ryosaku Kawada, Naoto Yokoyama, Genichi Sugihara, Toshiya Murai, Hidehiko Takahashi
      Abstract: The regulation of cue-induced craving for cigarettes is a key factor in smoking cessation. Outcomes of smoking cessation have been linked to self-efficacy, faith in one's own ability, in smokers. However, no study has examined the neural basis of self-efficacy during the control of craving. We examined whether self-efficacy can affect the neural response to smoking cues in smokers and ex-smokers using functional magnetic resonance imaging. During scanning, participants were instructed (1) to view smoking-related images passively, (2) to view the smoking-related images with a strategy focused on self-efficacy to control cue-induced craving or (3) to view neutral images. In smokers, the self-efficacy strategy significantly reduced self-reported craving. This strategy was related to increased activation in the rostral medial prefrontal cortex (rmPFC) and the pregenual anterior cingulate cortex in smokers compared with ex-smokers. Furthermore, smokers showed increased effective connectivity between rmPFC and hippocampus and between pregenual anterior cingulate cortex and parahippocampus gyrus when employing the self-efficacy strategy compared with ex-smokers. The magnitude of the rmPFC–hippocampus connectivity was positively correlated with self-reported self-efficacy. Our findings suggest that in smokers, self-efficacy is related to activation and connectivity in brain regions involved in regulating craving and self-assessment. The current study provides evidence for understanding the vunderlying cognitive and neurobiological mechanisms involved in the control of craving to smoke cigarettes.We examined whether self-efficacy can affect the neural response to smoking cues in smokers and ex-smokers using functional magnetic resonance imaging. In smokers, the self-efficacy strategy was related to increased activation in the rostral medial prefrontal cortex (rmPFC) and the pregenual anterior cingulate cortex (pgACC) and increased connectivity between rmPFC and hippocampus and between pgACC and parahippocampus gyrus. Our findings suggest that in smokers, self-efficacy is related to activation and connectivity in brain regions involved in regulating craving and self-assessment.
      PubDate: 2017-09-07T03:20:35.76393-05:0
      DOI: 10.1111/adb.12555
  • Neurotensin in the posterior thalamic paraventricular nucleus: inhibitor
           of pharmacologically relevant ethanol drinking
    • Authors: Surya Pandey; Preeti S. Badve, Genevieve R. Curtis, Sarah F. Leibowitz, Jessica R. Barson
      Abstract: Individuals prone to ethanol overconsumption may have preexisting neurochemical disturbances that contribute to their vulnerability. This study examined the paraventricular nucleus of the thalamus (PVT), a limbic structure recently shown to participate in ethanol intake. To identify individuals prone to ethanol overconsumption, we tested Long–Evans rats in behavioral paradigms and found high levels of vertical time (rearing behavior) in a novel activity chamber to be a consistent predictor of subsequent excessive 20 percent ethanol drinking under the intermittent access model. Examining neurochemicals in the PVT, we found before ethanol exposure that prone rats with high rearing, compared with non-prone rats, had significantly lower levels of neurotensin (NTS) mRNA and peptide in the posterior (pPVT) but not anterior (aPVT) subregion of the PVT. Our additional finding that ethanol intake has no significant impact on either rearing or NTS levels indicates that these measures, which are different in prone rats before ethanol consumption, remain stable after ethanol consumption. The possibility that NTS directly controls ethanol drinking is supported by our finding that NTS administration specifically suppresses ethanol drinking when injected into the pPVT but not aPVT, with this effect occurring exclusively in higher drinkers that presumably have lower endogenous levels of NTS. Further, an NTS antagonist in the pPVT augments intake in lower drinkers with presumably more endogenous NTS, while NTS in the pPVT inhibits novelty-induced rearing that predicts excessive drinking. Together, these results provide strong evidence that low endogenous levels of NTS in the pPVT contribute to an increased propensity toward excessive ethanol drinking.Rats prone to excessive ethanol drinking under the intermittent-access model show high levels of vertical time (rearing) in a novel activity chamber. In the posterior paraventricular nucleus of the thalamus (pPVT), rats identified through this behavior as prone to ethanol drinking show lower levels of the neuropeptide, neurotensin. Injection of neurotensin into the pPVT suppresses ethanol drinking while an antagonist increases it, pointing to this neuropeptide as a novel target for pharmacotherapeutic interventions for alcohol use disorder.
      PubDate: 2017-09-06T11:56:01.888492-05:
      DOI: 10.1111/adb.12546
  • Neural correlates of tobacco cue reactivity predict duration to lapse and
           continuous abstinence in smoking cessation treatment
    • Authors: Max M. Owens; James MacKillop, Joshua C. Gray, Steven R.H. Beach, Michael D. Stein, Raymond S. Niaura, Lawrence H. Sweet
      Abstract: It has been hypothesized that neural reactivity to drug cues in certain limbic/paralimbic regions of the brain is an indicator of addiction severity and a marker for likelihood of success in treatment. To address this question, in the current study, 32 participants (44 percent female) completed a functional magnetic resonance imaging cigarette cue exposure paradigm 2 hours after smoking, and then enrolled in a 9-week smoking cessation treatment program. Neural activation to smoking cues was measured in five a priori defined limbic/paralimbic regions previously implicated with cue reactivity across substances. These included regions of the ventral striatum, anterior cingulate cortex and amygdala. Cox proportional hazard modeling was conducted to predict the number of days to first smoking lapse by using neural activation in these regions. Greater neural activation during pre-treatment exposure to smoking cues in the right ventral striatum, the left amygdala, and the anterior cingulate was associated with longer periods of abstinence following cessation. A similar pattern was present for continuous abstinence for the full duration of treatment. While baseline levels of nicotine dependence were strongly associated with treatment outcome, activation in the right ventral striatum predicted duration of abstinence beyond level of nicotine dependence. These results suggest that pre-treatment reactivity to smoking cues in areas associated with cue reactivity may be associated with successfully maintaining abstinence during treatment. This is consistent with models that propose that as addiction becomes more severe, motivational processing shifts from regions that subserve reward salience and learning to regions responsible motor behavior and habit learning.Reactivity to cues associated with smoking is an established feature of tobacco use disorder. This human fMRI study predicts lapse and continuous abstinence in smoking cessation treatment using brain response to visual cigarette cues in the ventral striatum, amygdala and anterior cingulate cortex. Contrary to prior research, greater activation to smoking cues in these regions was associated with a longer duration of abstinence after quitting and greater likelihood of maintaining abstinence throughout treatment.
      PubDate: 2017-09-06T11:55:04.996452-05:
      DOI: 10.1111/adb.12549
  • 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
  • Neural mechanisms of extinguishing drug and pleasant cue associations in
           human addiction: role of the VMPFC
    • Authors: Anna B. Konova; Muhammad A. Parvaz, Vladimir Bernstein, Anna Zilverstand, Scott J. Moeller, Mauricio R. Delgado, Nelly Alia-Klein, Rita Z. Goldstein
      Abstract: The neurobiological mechanisms that underlie the resistance of drug cue associations to extinction in addiction remain unknown. Fear extinction critically depends on the ventromedial prefrontal cortex (VMPFC). Here, we tested if this same region plays a role in extinction of non-fear, drug and pleasant cue associations. Eighteen chronic cocaine users and 15 matched controls completed three functional MRI scans. Participants first learned to associate an abstract cue (the conditioned stimulus, CS) with a drug-related (CSD+) or pleasant (CSP+) image. Extinction immediately followed where each CS was repeatedly presented without the corresponding image. Participants underwent a second identical session 24 hours later to assess retention of extinction learning. Results showed that like fear extinction, non-fear-based extinction relies on the VMPFC. However, extinction-related changes in the VMPFC differed by cue valence and diagnosis. In controls, VMPFC activation to the CSD+ (which was unpleasant for participants) gradually increased as in fear extinction, while it decreased to the CSP+, consistent with a more general role of the VMPFC in flexible value updating. Supporting a specific role in extinction retention, we further observed a cross-day association between VMPFC activation and skin conductance, a classic index of conditioned responses. Finally, cocaine users showed VMPFC abnormalities for both CSs, which, in the case of the CSD+, correlated with craving. These data suggest a global deficit in extinction learning in this group that may hinder extinction-based treatment efforts. More broadly, these data show that the VMPFC, when functionally intact, supports extinction learning in diverse contexts in humans.In this 2-day fMRI study we find that, like fear extinction, non-fear based extinction relies on the ventromedial prefrontal cortex (VMPFC). However, we additionally find that extinction-related changes in the VMPFC differ by (1) what is being extinguished (drug-related versus pleasant cues) and (2) drug addiction diagnosis. While healthy individuals show progressive, cue-specific changes in VMPFC activation, chronic cocaine users do not, suggesting a global extinction-learning deficit in this group that may hinder extinction-based treatment efforts..
      PubDate: 2017-09-05T02:01:16.657524-05:
      DOI: 10.1111/adb.12545
  • Working memory and salivary brain-derived neurotrophic factor as
           developmental predictors of cocaine seeking in male and female rats
    • Authors: Chloe J. Jordan; Susan L. Andersen
      Abstract: Poor working memory is linked to future risk-taking behaviors. Lifelong risk of habitual drug use is highest in individuals who initiate use in early adolescence. We sought to determine in rats whether juvenile traits, specifically poor working memory and low salivary brain-derived neurotrophic factor (BDNF), are related to elevated cocaine taking and relapse in adolescence and adulthood. On postnatal day (P) 20, working memory was assessed using the novel object recognition task in male and female rats. Saliva was assayed at P20 for BDNF before cocaine self-administration on P28 [0.75 or 0.25 mg/kg/infusion for 30 days under a fixed-ratio (FR) 1 to FR5 schedule] and on P94 before relapse after 30-day abstinence in adulthood. A separate cohort of P28 male rats was assayed for object discrimination and BDNF in saliva and the medial prefrontal cortex and dorsolateral striatum. Novel object discrimination correlated positively with salivary BDNF on P20 and dorsolateral striatum levels, but negatively with medial prefrontal cortex BDNF in male rats. In female rats, P20 salivary BDNF negatively correlated with object discrimination. Salivary BDNF positively correlated across age in male rats. Male rats earned more cocaine (0.75 mg/kg) at FR5 and responded more at relapse than did female rats. These elevated relapse rates in male rats were significantly associated with P20 object discrimination and salivary BDNF. Relapse after 0.75 and 0.25 mg/kg in female rats correlated only with object discrimination. In conclusion, poor working memory and low salivary BDNF in juvenile male rats may represent biomarkers for later cocaine use. Further research is needed to identify biomarkers for risk in male rats.Lifelong risk for drug abuse is highest in individuals who initiate use in adolescence. Early identification of drug use risk is therefore critical. We find that in male rats, poor juvenile working memory and low salivary brain-derived neurotrophic factor (BDNF) are associated with elevated cocaine seeking in adolescence and adulthood. In female rats, only working memory is associated with later cocaine seeking. These findings suggest working memory and salivary BDNF may represent biomarkers for later cocaine abuse, although further research is needed in female rats.
      PubDate: 2017-08-31T05:30:54.816034-05:
      DOI: 10.1111/adb.12535
  • Young alcohol binge drinkers have elevated blood endotoxin, peripheral
           inflammation and low cortisol levels: neuropsychological correlations in
    • Authors: Laura Orio; María Antón, Inmaculada Concepción Rodríguez-Rojo, Ángeles Correas, Borja García-Bueno, Monserrat Corral, Fernando Rodríguez Fonseca, Luis Miguel García-Moreno, Fernando Maestú, Fernando Cadaveira
      Abstract: Alcohol binge drinking is a pattern of heavy alcohol consumption that is increasingly practiced by adolescents and young adults. Evidence indicates that alcohol binges induce peripheral inflammation and an exacerbated neuroimmune response that may participate in alcohol-induced cognitive/behavioral dysfunctions. Here, we recruited 20-year-old male and female university students who were identified as binge drinkers for at least 2 years. Compared with controls, young alcohol binge drinkers had elevated levels of blood endotoxin and upregulated markers of the toll-like receptor 4/NF-κB inflammatory pathway in peripheral blood mononuclear cells, together with pro-inflammatory cytokine/chemokine release, oxidative stress and lipid peroxidation. These changes positively correlate with the estimated blood alcohol levels achieved during alcohol binge intoxication and negatively correlate with the time elapsed from the last alcohol consumption. The immune/inflammatory changes were more prominent in female drinkers, who showed elevated levels of alcohol danger-associated molecules, such as high mobility group box 1, indicating that there are sex-related differences in the peripheral inflammatory response to alcohol. In contrast, cortisol levels were decreased in alcohol binge drinkers. Finally, higher levels of inflammatory markers, mainly monocyte chemoattractant protein-1, as well as LPS, high mobility group box 1, toll-like receptor 4, IL-6 and ciclooxygenase-2, correlated with worse scores on episodic memory and executive functioning tasks in female binge drinkers but not in male binge drinkers. These results emphasize possible risky consequences of alcohol use in binge episodes during young adulthood and call attention to sex-related differences in the alcohol-induced immune/inflammatory and neurocognitive responses.Young alcohol binge drinkers have elevated plasma endotoxin levels, immune over-activation, peripheral inflammation and decreased cortisol levels compared with controls. The TLR-4 mediated inflammatory response appears to be higher in female drinkers, who show danger products, such as HMGB1, in blood. Additionally, higher inflammation correlates with worse episodic memory and executive functioning in female but not male drinkers. Results emphasize the risky consequences of alcohol use in binge episodes and call attention to sex-related differences in the alcohol-induced inflammatory response.
      PubDate: 2017-08-25T06:55:41.803948-05:
      DOI: 10.1111/adb.12543
  • Chronic ethanol consumption: role of TLR3/TRIF-dependent signaling
    • Authors: Gizelle M. McCarthy; Anna S. Warden, Courtney R. Bridges, Yuri A. Blednov, R. Adron Harris
      Abstract: Chronic ethanol consumption stimulates neuroimmune signaling in the brain, and Toll-like receptor (TLR) activation plays a key role in ethanol-induced inflammation. However, it is unknown which of the TLR signaling pathways, the myeloid differentiation primary response gene 88 (MyD88) dependent or the TIR-domain-containing adapter-inducing interferon-β (TRIF) dependent, is activated in response to chronic ethanol. We used voluntary (every-other-day) chronic ethanol consumption in adult C57BL/6J mice and measured expression of TLRs and their signaling molecules immediately following consumption and 24 hours after removing alcohol. We focused on the prefrontal cortex where neuroimmune changes are the most robust and also investigated the nucleus accumbens and amygdala. Tlr mRNA and components of the TRIF-dependent pathway (mRNA and protein) were increased in the prefrontal cortex 24 hours after ethanol and Cxcl10 expression increased 0 hour after ethanol. Expression of Tlr3 and TRIF-related components increased in the nucleus accumbens, but slightly decreased in the amygdala. In addition, we demonstrate that the IKKε/TBK1 inhibitor Amlexanox decreases immune activation of TRIF-dependent pathway in the brain and reduces ethanol consumption, suggesting the TRIF-dependent pathway regulates drinking. Our results support the importance of TLR3 and the TRIF-dependent pathway in ethanol-induced neuroimmune signaling and suggest that this pathway could be a target in the treatment of alcohol use disorders.Chronic voluntary alcohol results in time-dependent changes in toll-like receptor pathways in the prefrontal cortex. These changes include increased expression of Tlr3, components of the TRIF-dependent pathway, and the interferon inducible gene Cxcl10. The TRIF-dependent pathway inhibitor Amlexanox reduces Cxcl10 induction in vivo and decreases ethanol consumption, suggesting a role for the TRIF pathway in the regulation of alcohol consumption.
      PubDate: 2017-08-25T06:41:36.335522-05:
      DOI: 10.1111/adb.12539
  • Acute calming effects of alcohol are associated with disruption of the
           salience network
    • Authors: Stephanie M. Gorka; K. Luan Phan, Emma Childs
      Abstract: The mood-altering properties of alcohol are a key motivation for drinking, and people commonly report that they drink alcohol to alleviate stress or to relax. To date, the neural processes associated with the self-reported calming effects of alcohol are not well understood. Existing data imply that alcohol may target and disrupt activity within anterior insula (aINS) and amygdala-based neural networks, which are regions implicated in threat detection and anxious responding. The aims of the current study were (1) to examine the acute effect of alcohol upon functional connectivity within aINS and amygdala circuits and (2) to assess relationships between alcohol effects on functional connectivity and self-reported subjective mood. Healthy men and women (N = 39) who reported regular binge drinking completed a within-subjects, double-blind, placebo-controlled pharmacological functional magnetic resonance imaging experiment with i.v. infusions of either alcohol or placebo. Infusion profiles were personalized for each participant and raised breath alcohol concentration to 80 mg percent. Before, during and after infusions, participants rated their subjective mood (stimulation, sedation and calm). Results showed that alcohol dampened functional connectivity between bilateral aINS seed-regions-of-interest and the dorsal anterior cingulate cortex (dACC), key nodes of the salience network. Additionally, the more that alcohol reduced right aINS-dACC functional connectivity, the calmer participants felt during alcohol administration. Alcohol had no effect on amygdala functional connectivity. These findings suggest that alcohol disrupts aINS-dACC functional connectivity, which may impair detection and appraisal of emotionally salient information and relate to acute relaxing effects of the drug.It is thought that alcohol may produce anxiolytic effects by downregulating limbic activity and disrupting functional connections between frontolimbic circuits that mediate salience processing. Here we show that alcohol infusions dampened functional connectivity between bilateral anterior insula and the dorsal anterior cingulate cortex, key nodes of the salience network, among hazardous drinkers. Furthermore, the more that alcohol reduced right anterior insula-dorsal anterior cingulate cortex connectivity, the calmer participants felt during alcohol administration. Our findings suggest that alcohol disrupts salience determination, which may contribute to feelings of relaxation while intoxicated.
      PubDate: 2017-08-09T01:55:25.959195-05:
      DOI: 10.1111/adb.12537
  • Differential stimulus control of drug-seeking: multimodal reinstatement
    • Authors: Seth R. Batten; Joshua S. Beckmann
      Abstract: In animal models of substance-use disorder, individuals that repeatedly self-administer drugs of abuse have long-lasting neuronal adaptations that do not occur ostensibly in control animals only exposed to natural reinforcers (e.g. food). Because any treatment for substance-use disorder will be given to individuals with drug-taking histories, adequate dissociation of the specific neurobehavioral mechanisms underlying drug reinforcement, natural reinforcement and their associated cue effects requires an experimental model that exposes individuals to both reinforcer conditions, along with their associated stimuli. Furthermore, contingent stimuli that reinforce drug seeking through second-order relationships may produce reinstatement of drug seeking through different neurobehavioral means than non-contingent exposure to stimuli that signal the availability of a drug reinforcer, effectively producing different modes of stimulus-induced reinstatement. Toward experimental isolation of the relationships mentioned, herein, we used a within-session multiple schedule of reinforcement containing both discriminative (SD) and conditioned (CS) stimuli to study stimulus control of drug-taking and food-taking behavior, along with how these functionally distinct cues may differentially reinstate drug-seeking and food-seeking behavior within a single animal. We demonstrate specific stimulus control over drug and food taking; furthermore, we demonstrate that the same stimulus (i.e. cue light) operating as an SD or CS produced differential reinstatement of drug-taking and food-taking behavior. The results suggest that contingent CSs and non-contingent SDs produce reinstatement through different neurobehavioral processes and, within-session multiple schedules, can be used to study different modes of specific stimulus control over drug and food seeking in a single animal with both drug-taking and food-taking history.We used a multiple schedule to demonstrate specific stimulus control over drug and food taking. Furthermore, we demonstrated that the same stimulus operating as a discriminative or conditioned stimulus produced differential reinstatement of drug and food seeking. The results suggest that discriminative and conditioned stimuli produce reinstatement through different neurobehavioral processes, and multiple schedules can be used to study different modes of specific stimulus control over drug and food seeking within individuals.
      PubDate: 2017-08-09T01:50:35.3045-05:00
      DOI: 10.1111/adb.12544
  • Prenatal androgen receptor activation determines adult alcohol and water
           drinking in a sex-specific way
    • Authors: Sabine E. Huber; Iulia Zoicas, Martin Reichel, Christiane Mühle, Christian Büttner, Arif B. Ekici, Volker Eulenburg, Bernd Lenz, Johannes Kornhuber, Christian P. Müller
      Abstract: Alcohol use disorders are major psychiatric disorders. Correlational studies in humans suggested organizational hormonal effects during embryonic development as a risk factor for adult alcohol dependence. Permanent changes can be induced by the activity of sex hormones, like testosterone. Here, we demonstrate a relationship between prenatal androgen receptor (AR)-activation and adult alcohol as well as water drinking in mice in a sex-dependent fashion. Prenatal AR inhibition using the antagonist flutamide decreased adult male alcohol consumption. In contrast, prenatal AR activation by dihydrotestosterone (DHT) led to an increase in adult alcohol consumption in females. These effects were different in adult water drinking, flutamide increased water consumption in females and DHT increased water consumption in males. Prenatal flutamide reduced locomotion and anxiety in adult males but was ineffective in females. We found that prenatal AR activation controls adult levels of monoaminergic modulatory transmitters in the brain and blood hormone levels in a sex-specific way. RNA-Seq analysis confirmed a prenatal AR mediated control of adult expression of alcohol drinking-related genes like Bdnf and Per2. These findings demonstrate that prenatal androgen activity is a risk factor for the establishment of alcohol consumption in adults by its organizational effects.Prenatal sex hormones have organizational effects and have been implicated in alcohol dependence. We found that prenatal manipulation of the hormonal milieu with dihydrotestosterone leads to a highly increased alcohol consumption in female mice, while it has no effect in male mice. We further demonstrate that androgen-receptor activation controls adult levels of monoamines and influences behavior in a sex-specific way.
      PubDate: 2017-08-04T05:15:53.005503-05:
      DOI: 10.1111/adb.12540
  • Addiction-related interactions of pregabalin with morphine in mice and
           humans: reinforcing and inhibiting effects
    • Authors: Elena Vashchinkina; Ossi Piippo, Olga Vekovischeva, Evgeny Krupitsky, Ruslan Ilyuk, Nikholay Neznanov, Kirill Kazankov, Igor Zaplatkin, Esa R. Korpi
      Abstract: The gabapentinoid pregabalin is a rapid-acting anxiolytic and analgesic, possibly suitable in supervised opioid detoxification. However, clinicians have been cautious in using it because of its unknown addictive risk and rising number of mortalities after pregabalin self-medication in opioid abusers. Here, we studied interactions of pregabalin and morphine on reward functions of the dopamine system in mice and the efficacy of pregabalin on withdrawal in opioid addicts. After the treatment of mice with pregabalin and morphine, we used electrophysiology to study neuroplasticity in midbrain slices, self-administration and conditioned place preference tests to investigate the rewarding potential of pregabalin and naloxone-precipitated morphine withdrawal to evaluate opioid withdrawal symptoms. Further, we ran a pilot single-blind, randomized, controlled trial (34 heroin addicts) to evaluate the efficacy and safety of pregabalin in the treatment of opioid withdrawal syndrome. Pregabalin alone did not induce glutamate receptor neuroplasticity of dopamine neurons in the ventral tegmental area, but pre-treatment with pregabalin suppressed morphine-induced neuroplasticity, hyperlocomotion and morphine self-administration. Pregabalin administration after chronic morphine exposure failed to induce any rewarding effects. Instead, pregabalin suppressed withdrawal symptoms in both morphine-treated mice and opioid addicts and was well tolerated. Intriguingly, pregabalin administration after a low dose of morphine strongly facilitated ventral tegmental area neuroplasticity and led to increased conditioned place preference. Pregabalin appears to have the efficacy to counteract both reinforcing and withdrawal effects of opioids, but it also has a potentiating effect when given to mice with existing opioid levels.In this translational study, we investigated the interactions of pregabalin and morphine on reward functions of the dopamine system in mice and the efficacy of pregabalin on withdrawal in opioid addicts. In mice, acute pregabalin suppressed morphine-induced long-term potentiation in the dopamine neurons and withdrawal signs, but pregabalin after morphine administration facilitated this long-term potentiation and rewarding behavior. Chronic experience of morphine in the past did not change the rewarding effects of pregabalin. In humans, pregabalin suppressed withdrawal signs and was well tolerated.
      PubDate: 2017-07-25T02:31:40.796676-05:
      DOI: 10.1111/adb.12538
  • Methamphetamine promotes habitual action and alters the density of
           striatal glutamate receptor and vesicular proteins in dorsal striatum
    • Authors: Teri M. Furlong; Laura H. Corbit, Robert A. Brown, Bernard W. Balleine
      Abstract: Goal-directed actions are controlled by the value of the consequences they produce and so increase when what they produce is valuable and decrease when it is not. With continued invariant practice, however, goal-directed actions can become habits, controlled not by their consequences but by antecedent, reward-related states and stimuli. Here, we show that pre-exposure to methamphetamine (METH) caused abnormally rapid development of habitual control. Furthermore, these drug-induced habits differed strikingly from conventional habits; we found that they were insensitive both to changes in reward value and to the effects of negative feedback. In addition to these behavioral changes, METH exposure produced bidirectional changes to synaptic proteins in the dorsal striatum. In the dorsomedial striatum, a structure critical for goal-directed action, METH exposure was associated with a reduction in glutamate receptor and glutamate vesicular proteins, whereas in the dorsolateral striatum, a region that has previously been implicated in habit learning, there was an increase in these proteins. Together, these results indicate that METH exposure promotes habitual control of action that appears to be the result of bidirectional changes in glutamatergic transmission in the circuits underlying goal-directed and habit-based learning.We demonstrated that exposure to methamphetamine (METH) accelerates habitual control of behavior and alters levels of glutamate-related proteins in dorsal striatum. Using an outcome-devaluation instrumental task, we showed that the actions of METH exposed rats were insensitive to changes in reward value and to negative feedback. METH also produced bidirectional changes in glutamate receptor and glutamate vesicular proteins in dorsomedial and dorsolateral striatum suggesting that METH alters glutamate transmission in circuits underlying goal-directed and habit-based learning.
      PubDate: 2017-07-14T01:10:41.704333-05:
      DOI: 10.1111/adb.12534
  • Neuronal representation of individual heroin choices in the orbitofrontal
    • Authors: Karine Guillem; Viridiana Brenot, Audrey Durand, Serge H. Ahmed
      Abstract: Drug addiction is a harmful preference for drug use over and at the expense of other non-drug-related activities. We previously identified in the rat orbitofrontal cortex (OFC) a mechanism that influences individual preferences between cocaine use and an alternative action rewarded by a non-drug reward (i.e. sweet water). Here, we sought to test the generality of this mechanism to a different addictive drug, heroin. OFC neuronal activity was recorded while rats responded for heroin or the alternative non-drug reward separately or while they chose between the two. First, we found that heroin-rewarded and sweet water-rewarded actions were encoded by two non-overlapping OFC neuronal populations and that the relative size of the heroin population represented individual drug choices. Second, OFC neurons encoding the preferred action—which was the non-drug action in the large majority of individuals—progressively fired more than non-preferred action-coding neurons 1 second after the onset of choice trials and around 1 second before the preferred action was actually chosen, suggesting a pre-choice neuronal competition for action selection. Together with a previous study on cocaine choice, the present study on heroin choice reveals important commonalities in how OFC neurons encode individual drug choices and preferences across different classes of drugs. It also reveals some drug-specific differences in OFC encoding activity. Notably, the proportion of neurons that non-selectively encode both the drug and the non-drug reward was higher when the drug was heroin (present study) than when it was cocaine (previous study). We will discuss the potential functional significance of these commonalities and differences in OFC neuronal activity across different drugs for understanding drug choice.We previously found that the orbitofrontal cortex (OFC) activity influences individual preferences between cocaine use and an alternative non-drug reward. Here, we sought to test the generality of this mechanism to a different addictive drug, heroin. Like with cocaine, OFC neurons encode individual heroin choices. However, there were also some drug-specific differences in OFC encoding suggesting that the OFC would not only encode preference but also resemblance between the drug and non-drug options available for choice.
      PubDate: 2017-07-13T00:42:12.679363-05:
      DOI: 10.1111/adb.12536
  • 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
      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
  • 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
      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
  • 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
      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
  • A new generation of mTORC1 inhibitor attenuates alcohol intake and reward
           in mice
    • Authors: Nadege Morisot; Christopher J. Novotny, Kevan M. Shokat, Dorit Ron
      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
      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
  • 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
      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
      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
  • Noradrenergic signaling in the VTA modulates cocaine craving
    • Authors: Wojciech Barnaba Solecki; Klaudia Szklarczyk, Kamil Pradel, Krystyna Kwiatkowska, Grzegorz Dobrzański, Ryszard Przewłocki
      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
  • 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
      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
  • Locomotor sensitization is expressed by ghrelin and D1 dopamine receptor
           agonist in the nucleus accumbens core in amphetamine pre-exposed rat
    • Authors: Ju Kyong Jang; Wha Young Kim, Bo Ram Cho, Jung Won Lee, Jeong-Hoon Kim
      Abstract: Ghrelin modulates mesolimbic dopaminergic pathways in the brain in addition to its role in feeding. We investigated what roles ghrelin in the nucleus accumbens (NAcc) core may play in mediating locomotor activating effects of amphetamine (AMPH). First, when rats were administered with AMPH (1 mg/kg, i.p.) following a bilateral microinjection of ghrelin (0.1 or 0.5 μg/side) into the NAcc core, their locomotor activity was significantly enhanced, while these effects were blocked by co-microinjection of ghrelin receptor antagonist (0.5 μg/side) into this site. Second, we pre-exposed rats to saline or amphetamine (1 mg/kg, i.p.) every 2 to 3 days for a total of four times. After 2 weeks of drug-free withdrawal period, we examined the effect of saline, ghrelin (0.5 μg/side), D1 dopamine receptor agonist, SKF81297 (0.5 μg/side) or ghrelin (0.5 μg/side) + SKF81297 (0.5 μg/side) directly microinjected into the NAcc core on locomotor activity. When we measured rats' locomotor activity for 1 hour immediately following microinjections, only ghrelin + SKF81297 produces sensitized locomotor activity, while all others have no effects. These results suggest that ghrelin may have a distinct role in the NAcc core to provoke the sensitized locomotor activity induced by psychomotor stimulants, and further, it may produce these effects by interaction with D1 dopamine receptors.Ghrelin modulates mesolimbic dopaminergic pathways in the brain in addition to its role in feeding. Here, we showed that ghrelin in the nucleus accumbens core significantly enhanced acute amphetamine-induced locomotor activity. Further, ghrelin when co-microinjected into this site with SKF 81297 produced sensitized locomotor activity in amphetamine pre-exposed rats. These results suggest that ghrelin has a distinct role in the nucleus accumbens core to provoke the sensitized locomotor activity induced by psychomotor stimulants, with the help of D1 dopamine receptors.
      PubDate: 2017-06-21T01:55:28.631528-05:
      DOI: 10.1111/adb.12533
  • 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
      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
  • 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
      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
  • Issue Information
    • Pages: 1473 - 1474
      Abstract: No abstract is available for this article.
      PubDate: 2017-10-27T02:26:04.648672-05:
      DOI: 10.1111/adb.12456
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