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Publisher: John Wiley and Sons   (Total: 1583 journals)

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Showing 1 - 200 of 1583 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 11, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 53, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 43, SJR: 0.547, h-index: 30)
ACEP NOW     Free  
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 50, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 133, 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: 5, SJR: 0.112, h-index: 1)
Acta Paediatrica     Hybrid Journal   (Followers: 54, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 7, 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: 5, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 2)
Addiction     Hybrid Journal   (Followers: 32, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 12, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 24, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 24, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 48, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 247, 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: 4, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 4)
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: 19)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 12)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 9)
African Development Review     Hybrid Journal   (Followers: 33, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 14, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 9, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 6, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 14, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 44, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 28, 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: 49, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 129, 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: 89, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 28, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 30, 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: 15, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 3, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 5, SJR: 2.315, h-index: 79)
American J. of Orthopsychiatry     Hybrid Journal   (Followers: 4, SJR: 0.756, h-index: 69)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 35, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 237, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 14, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 3, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 15, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 115, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 11, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 15)
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: 154)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 205, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 34, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 5, 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: 8, 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: 42, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 2, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 9, SJR: 0.336, h-index: 23)
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5, SJR: 2.389, h-index: 189)
Annual Bulletin of Historical Literature     Hybrid Journal   (Followers: 12)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 24, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 16, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 14)
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: 92, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 45, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 6, 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: 66, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 6, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 128, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 47, 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: 13, 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: 34, 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: 14, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 24, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 4, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 4)
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: 203, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 48, 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: 13)
Asia & the Pacific Policy Studies     Open Access   (Followers: 15)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 321, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 7, 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: 3, 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: 3, 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: 4, 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: 13, 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: 12, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 10, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 7, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 7, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 13, 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: 42, 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: 6, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 4, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 22, 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: 13, SJR: 0.203, h-index: 14)
Australian J. of Psychology     Hybrid Journal   (Followers: 16, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 383, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 4, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 64, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 11, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 19, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 31, 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: 9, 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: 3, 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: 7, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 21, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 9, 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: 14, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 2, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 44, 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: 45, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 134, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 13, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 17, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 10, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 33, 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: 5, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)

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Journal Cover Addiction Biology
  [SJR: 2.091]   [H-I: 57]   [12 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  [1583 journals]
  • Nicotine self-administration reverses cognitive deficits in a rat model
           for schizophrenia
    • Authors: Uta Waterhouse; Katharine A. Brennan, Bart A. Ellenbroek
      Abstract: High comorbidity between schizophrenia and tobacco addiction has been well established. Explanatory theories include nicotine as a cognitive enhancer ameliorating symptoms of schizophrenia and underlying shared substrates increasing susceptibility to addiction in these individuals. To test these non-mutually exclusive theories, the maternal immune activation (MIA) model was utilized. To this end, pregnant Sprague Dawley rats were subcutaneously injected with a bacterial endotoxin, lipopolysaccharide (0.5 mg/kg), on gestation days 10 and 11. Selective attention and working memory in adult male offspring were subsequently assessed using the latent inhibition and delayed non-matching to sample paradigms both before and after nicotine or saline self-administration. MIA led to deficits in both latent inhibition and delayed non-matching to sample in male offspring. Further, these animals showed a small but significantly increased responding for nicotine during self-administration acquisition, although there was no difference in dose–response effect or in progressive ratio testing. However, nicotine, but not saline self-administration, significantly ameliorated the cognitive deficits induced by MIA. While the male offspring of mothers prenatally exposed to lipopolysaccharide was only slightly more sensitive to the reinforcing effects of nicotine, after self-administration, the MIA-induced cognitive deficits significantly improved. These data lend support for the self-medication hypothesis of schizophrenia.Prenatal lipopolysaccharide (LPS) induces cognitive deficits in male offspring. Prenatal LPS does not enhance reinforcing properties of nicotine. Nicotine reverses cognitive deficits induced by prenatal LPS treatment.
      PubDate: 2017-05-12T02:40:51.7157-05:00
      DOI: 10.1111/adb.12517
  • Altered interhemispheric resting-state functional connectivity in young
           male smokers
    • Authors: Dahua Yu; Kai Yuan, Yanzhi Bi, Lin Luo, Jinquan Zhai, Bo Liu, Yangding Li, Jiadong Cheng, Yanyan Guan, Ting Xue, Limei Bu, Shaoping Su, Yao Ma, Wei Qin, Jie Tian, Xiaoqi Lu
      Abstract: With the help of advanced neuroimaging approaches, previous studies revealed structural and functional brain changes in smokers compared with healthy non-smokers. Homotopic resting-state functional connectivity between the corresponding regions in cerebral hemispheres may help us to deduce the changes of functional coordination in the whole brain of young male smokers. Functional homotopy reflects an essential aspect of brain function and communication between the left and right cerebral hemispheres, which is important for the integrity of brain function. However, few studies used voxel mirrored homotopic connectivity (VMHC) method to investigate the changes of homotopic connectivity in young male smokers. Twenty-seven young male smokers and 27 matched healthy male non-smokers were recruited in our study. Compared with healthy male non-smokers, young male smokers showed decreased VMHC values in the insula and putamen, and increased VMHC values in the prefrontal cortex. Correlation analysis demonstrated that there were significant positive correlations between the average VMHC values of the prefrontal cortex and pack-years in young male smokers. In addition, significant negative correlation was found between the average VMHC values in the insula and pack-years. Our results revealed the disrupted homotopic resting-state functional connectivity in young male smokers. The novel findings may extend our understanding of smoking.Compared with healthy male non-smokers, young male smokers showed decreased voxel mirrored homotopic voxel (VMHC) values in the insula and putamen, and increased VMHC values in the prefrontal cortex. Correlation analysis demonstrated that there were significant correlations between pack-years and the average VMHC values of the prefrontal cortex and insula. Our results revealed the disrupted homotopic resting-state functional connectivity in young male smokers, which may extend our understanding of smoking.
      PubDate: 2017-05-05T04:34:40.256403-05:
      DOI: 10.1111/adb.12515
  • Dopamine D1 or D2 receptor-expressing neurons in the central nervous
    • Authors: Xiaoyan Wei; Tengfei Ma, Yifeng Cheng, Cathy C.Y. Huang, Xuehua Wang, Jiayi Lu, Jun Wang
      Abstract: Dopamine signals mainly through D1 receptors (D1Rs) and D2 receptors (D2Rs); D1R-expressing or D2R-expressing neurons contribute to distinct reward and addictive behaviors. Traditionally, transgenic mice expressing green fluorescent protein (GFP) under D1R or D2R promoters are used for fluorescent verification in electrophysiology studies, whereas Cre mice are employed for behavioral research. However, it is unknown whether the same neuronal populations are targeted in GFP and Cre mice. Additionally, while D1Rs and D2Rs are known to be expressed in different striatal neurons, their expression patterns outside the striatum remain unclear. The present study addressed these two questions by using several transgenic mouse lines expressing fluorescent proteins (GFP or tdTomato) or Cre under the control of D1R or D2R promoters. We found a high degree of overlap between GFP-positive and Cre-positive neurons in the striatum and hippocampus. Additionally, we discovered that D1Rs and D2Rs were highly segregated in the orbitofrontal cortex, prefrontal cortex, dorsal and ventral hippocampus, and amygdala: ~4–34 percent of neurons co-expressed these receptors. Importantly, slice electrophysiological studies demonstrated that D1R-positive and D1R-negative hippocampal neurons were functionally distinct in a mouse line generated by crossing Drd1a-Cre mice with a Cre reporter Ai14 line. Lastly, we discovered that chronic alcohol intake differentially altered D1R-positive and D2R-positive neuron excitability in the ventral CA1. These data suggest that GFP and Cre mice target the same populations of striatal neurons, D1R-expressing or D2R-expressing neurons are highly segregated outside the striatum, and these neurons in the ventral hippocampal may exert distinct roles in alcohol addiction.D1(D2)-GFP and D1(D2)-Cre mice target the same populations of striatal neurons. D1R-expressing and D2R-expressing neurons are highly segregated in the cortex, hippocampus, and amygdala. Excessive alcohol consumption distinctly regulates excitability of D1R-expressing and D2R-expressing ventral CA1 neurons.
      PubDate: 2017-04-24T05:04:46.143109-05:
      DOI: 10.1111/adb.12512
  • Levodopa prevents the reinstatement of cocaine self-administration in rats
           via potentiation of dopamine release in the medial prefrontal cortex
    • Authors: Silvia Antinori; Liana Fattore, Pierluigi Saba, Walter Fratta, Gian Luigi Gessa, Paola Devoto
      Abstract: Dopamine agonists have been proposed as therapeutic tools for cocaine addiction. We have recently demonstrated that indirect dopamine agonists, including levodopa (L-DOPA), markedly increase cocaine-induced dopamine release in the medial prefrontal cortex (mPFC) of rats leading to the suppression of cocaine-seeking behavior. This study was aimed to understand the behavioral and neurochemical effects of L-DOPA on cocaine-taking and cocaine-seeking in rats. After reaching a stable pattern of intravenous cocaine self-administration under a continuous fixed ratio (FR-1) schedule of reinforcement, male rats were treated with L-DOPA at different steps of the self-administration protocol. We found that L-DOPA reduced cocaine self-administration under FR-1 schedule of reinforcement and decreased the breaking points and the amount of cocaine self-administered under the progressive ratio schedule of reinforcement. Levodopa also decreased cocaine-seeking behavior both in a saline substitution test and in the cue priming-induced reinstatement test, without affecting general motor activity. Importantly, L-DOPA greatly potentiated cocaine-induced dopamine release in the mPFC of self-administering rats while reducing their cocaine intake. In the same brain area, L-DOPA also increased dopamine levels during cue priming-induced reinstatement of cocaine-seeking behavior. The potentiating effect was also evident in the mPFC but not nucleus accumbens core of drug-naïve rats passively administered with cocaine. Altogether, these findings demonstrate that L-DOPA efficaciously reduces the reinforcing and motivational effects of cocaine likely potentiating dopamine transmission in the mPFC. Its ability to prevent cue priming-induced reinstatement of cocaine-seeking suggests that it might be effective in reducing the risk to relapse to cocaine in abstinent patients.Systemic administration of levodopa (L-DOPA) potentiates cocaine-induced dopamine (DA) release in the rat medial prefrontal cortex (mPFC) during cocaine self-administration and contextually reduces cocaine-taking behavior. In the same brain area, after extinction of self-administration, L-DOPA administration increases DA levels and inhibits cocaine-seeking behavior during cue priming-induced reinstatement. Its ability to prevent cue priming-induced reinstatement of cocaine-seeking suggests that it might be effective in reducing the risk to relapse to cocaine in abstinent patients.
      PubDate: 2017-04-21T05:20:46.265804-05:
      DOI: 10.1111/adb.12509
  • Intravenous self-administration of benzydamine, a non-steroidal
           anti-inflammatory drug with a central cannabinoidergic mechanism of action
    • Authors: Riccardo Avvisati; Maria Meringolo, Emiliana Stendardo, Elisa Malavasi, Silvia Marinelli, Aldo Badiani
      Abstract: Benzydamine (BZY) is a non-steroidal anti-inflammatory drug used for the topical treatment of inflammations of the oral and vaginal mucosae. Virtually nothing is known about the central pharmacological actions of BZY. Yet there are reports of voluntary systemic overdosage of BZY in drug addicts, resulting in a euphoric, hallucinatory state. In the present study, we investigated the reinforcing properties of BZY in a rat self-administration paradigm. We found that BZY has a powerful reinforcing effect and that this effect is greatly facilitated in animals that already had substance experience, having previously self-administered heroin and cocaine, indicating cross sensitization between BZY and other common drugs of abuse. We then assessed the effect of BZY on prelimbic cortex-to-nucleus accumbens glutamatergic transmission, using field recordings in rat parasagittal brain slices. BZY dose-dependently reduced both field excitatory post synaptic potential amplitude and paired pulse ratio, suggesting a presynaptic mechanism of action. Similarly to the in vivo paradigm, also the electrophysiological effects of BZY were potentiated in slices from animals that had undergone cocaine and heroin self-administration. Furthermore, BZY-induced Long Term Depression (LTD)-like responses in the prelimbic cortex-to-nucleus accumbens circuitry were significantly reduced in the presence of the CB1 receptor antagonist AM251. These findings provide firm evidence of the abuse liability of BZY and suggest a possible cannabinoidergic mechanism of action. Further research is needed in order to give insights into the molecular mechanism underlying BZY psychoactive and reinforcing effects, to better understand its abuse potential.Abuse of the anti-inflammatory drug benzydamine (BZY) has been reported, especially in drug addicts, but experimental evidence is lacking. We report here that BZY (1) has powerful reinforcing effects in the rat and these effects are facilitated by previous exposure to cocaine and heroin and (2) induces long-term depression of cortico-accumbens synaptic transmission, a phenomenon partially blocked by CB1 receptor antagonism. Our findings provide firm evidence of the addictive potential of BZY and suggest a cannabinoidergic mechanism of action.
      PubDate: 2017-04-21T05:05:34.721177-05:
      DOI: 10.1111/adb.12516
  • Pooled analysis of three randomized, double-blind, placebo controlled
           trials with rimonabant for smoking cessation
    • Authors: Jason D. Robinson; Paul M. Cinciripini, Maher Karam-Hage, Henri-Jean Aubin, Lowell C. Dale, Raymond Niaura, Robert M. Anthenelli,
      Abstract: Despite the withdrawal of CB1 antagonists, such as rimonabant, from the market and from active clinical development because of concerns about their side effect profiles, research suggests that the endocannabinoid system may play an important role in modulating nicotine's effects. We report the combined results, using a pooled analysis, of three previously unpublished trials assessing rimonabant as a smoking cessation pharmacotherapy conducted between 2002 and 2004. Smokers (n = 2097) motivated to quit were enrolled in three randomized, double-blind, placebo-controlled trials, STRATUS EU, US, and META, which consisted of a 10-week treatment period with either rimonabant 20 mg (n = 789), 5 mg (n = 518; used in only two of the three studies), or placebo (n = 790), in conjunction with brief counseling. The impact of drug on prolonged abstinence and adverse events was examined at 8 weeks (end-of-treatment) and at 48 weeks (available for STRATUS EU and US) after the targeted quit date. Rimonabant 20 mg resulted in significantly higher abstinence at end-of-treatment and at 48 weeks post-targeted quit date compared with placebo, while rimonabant 5 mg and placebo did not differ. Serious AEs did not differ by drug group. The 20 mg rimonabant dose, compared with placebo, produced increased nausea, diarrhea, anxiety symptoms, hyporexia, and vomiting, and decreased headache, constipation, and cough. These results support rimonabant 20 mg as a modestly effective aid for smoking cessation. Although work on CB1 antagonists such as rimonabant has mostly been stopped because of unacceptable adverse events, these results may inform and spur the development of other endocannabinoids for smoking cessation.We conducted pooled analysis of three previously unpublished trials (STRATUS EU, US, and META) assessing 10 weeks on the CB1 antagonist rimonabant 20 and 5 mg or placebo for smoking cessation. Rimonabant 20 mg resulted in significantly higher abstinence than the 5 mg or placebo dose but also produced increased nausea, diarrhea, anxiety symptoms, hyporexia, and vomiting, and decreased headache, constipation, and cough, compared with placebo. These results may inform and spur the development of other endocannabinoids for smoking cessation.
      PubDate: 2017-04-21T04:55:32.851343-05:
      DOI: 10.1111/adb.12508
  • Nicotine-induced molecular alterations are modulated by GABAB receptor
    • Authors: Andres P. Varani; Valeria T. Pedrón, Amira J. Aon, Christian Höcht, Gabriela B. Acosta, Bernhard Bettler, Graciela N. Balerio
      Abstract: It has been demonstrated that GABAB receptors modulate nicotine (NIC) reward effect; nevertheless, the mechanism implicated is not well known. In this regard, we evaluated the involvement of GABAB receptors on the behavioral, neurochemical, biochemical and molecular alterations associated with the rewarding effects induced by NIC in mice, from a pharmacological and genetic approach. NIC-induced rewarding properties (0.5 mg/kg, subcutaneously, sc) were evaluated by conditioned place preference (CPP) paradigm. CPP has three phases: preconditioning, conditioning and postconditioning. GABAB receptor antagonist 2-hydroxysaclofen (0.25, 0.5 and 1 mg/kg; intraperitoneally, ip) or the GABAB receptor agonist baclofen (3 mg/kg; ip) was injected before NIC during the conditioning phase. GABAB1 knockout (GABAB1KO) mice received NIC during the conditioning phase. Vehicle and wild-type controls were employed. Neurochemical (dopamine, serotonin and their metabolites), biochemical (nicotinic receptor α4β2, α4β2nAChRs) and molecular (c-Fos) alterations induced by NIC were analyzed after the postconditioning phase by high-performance liquid chromatography (HPLC), receptor-ligand binding assays and immunohistochemistry, respectively, in nucleus accumbens (Acb), prefrontal cortex (PFC) and ventral tegmental area (VTA). NIC induced rewarding effects in the CPP paradigm and increased dopamine levels in Acb and PFC, α4β2nAChRs density in VTA and c-Fos expression in Acb shell (AcbSh), VTA and PFC. We showed that behavioral, neurochemical, biochemical and molecular alterations induced by NIC were prevented by baclofen. However, in 2-hydroxysaclofen pretreated and GABAB1KO mice, these alterations were potentiated, suggesting that GABAB receptor activity is necessary to control alterations induced by NIC-induced rewarding effects. Therefore, the present findings provided important contributions to the mechanisms implicated in NIC-induced rewarding effects.Nicotine induced rewarding effects in the conditioned place preference paradigm and increased dopamine levels in Acb and PFC, α4β2nAChRs density in VTA and c-Fos expression in Acb shell, VTA and PFC. Baclofen prevented the behavioral, neurochemical, biochemical and molecular alterations induced by NIC. However, in saclofen pretreated and GABAB1KO mice, these alterations were potentiated. These results suggest that GABAB receptor activity is necessary to control alterations induced by NIC-induced rewarding effects.
      PubDate: 2017-04-17T06:40:38.581614-05:
      DOI: 10.1111/adb.12506
  • Suvorexant, an orexin/hypocretin receptor antagonist, attenuates
           motivational and hedonic properties of cocaine
    • Authors: Taylor A. Gentile; Steven J. Simmons, David J. Barker, Jessica K. Shaw, Rodrigo A. España, John W. Muschamp
      Abstract: Orexins (‘hypocretins’) are peptides produced by neurons of the hypothalamus that project to structures implicated in reward and emotion processing. Converging evidence demonstrates functional roles of orexin signaling in arousal, sleep/wakefulness and motivated behaviors for natural and drug rewards. Suvorexant, a dual orexin receptor antagonist, recently received approval from the US Food and Drug Administration to treat insomnia. In Experiment 1, rats self-administered cocaine under a progressive-ratio schedule of reinforcement and the effects of suvorexant on motivation to self-administer cocaine were measured. In Experiment 2, the effects of suvorexant on cocaine reward were assessed by using a place conditioning paradigm, and 50-kHz ultrasonic vocalizations were also recorded to track changes in hedonic reactivity to cocaine. To rule out potentially confounding effects of suvorexant-induced somnolence, locomotor activity was also measured. In Experiment 3, the effects of suvorexant on cocaine-evoked elevations in ventral striatal dopamine were examined. Data reveal that suvorexant (i) reduced the number of cocaine infusions earned during progressive-ratio self-administration; (ii) attenuated initial positive hedonic reactivity to cocaine and prevented cocaine place preference; (iii) did not affect cocaine-induced hyperlocomotion and (iv) reduced cocaine-induced elevations in extracellular ventral striatal dopamine. The present study examined the therapeutic potential of suvorexant in rodent models of cocaine use disorder. These results contribute toward a growing literature supporting therapeutic roles of orexin receptor antagonists in treating substance use disorders.Our experiments found that suvorexant, the first-in-class clinically available dual hypocretin/receptor antagonist, reduces cocaine-seeking motivation in rats. Additionally, suvorexant was found to augment hedonic reactivity to systemically injected cocaine and attenuate cocaine-elicited elevations in ventral striatal dopamine release. Collectively, these findings contribute to developing literature positioning hypocretin/orexin receptor antagonists as possible adjunct therapies for treating substance use disorders in humans.
      PubDate: 2017-04-17T06:40:31.807719-05:
      DOI: 10.1111/adb.12507
  • A paradigm for examining stress effects on alcohol-motivated behaviors in
           participants with alcohol use disorder
    • Authors: Mary E. McCaul; Gary S. Wand, Elise M. Weerts, Xiaoqiang Xu
      Abstract: Although epidemiological research has shown an increase in drinking following stressors and trauma, limited paradigms have been validated to study the relationship between stress and drinking in the human laboratory. The current study developed a progressive ratio (PR) operant procedure to examine the effects of psychosocial stress on alcohol craving and several alcohol-motivated behaviors in persons with alcohol use disorder. Current heavy, nontreatment-seeking drinkers (N = 30) were media-recruited and completed a comprehensive assessment of recent drinking, mood and health. Participants were admitted to the clinical research unit and underwent 4-day, physician-monitored alcohol abstinence. On days 4 and 5, participants underwent the Trier Social Stress Test or a neutral session in random order followed by the alcohol-motivated response (AMR) procedure in which subjects worked for money or alcohol under a PR operant procedure. Subjects received earned money vouchers or alcohol at the conclusion of the session. The Trier Social Stress Test increased alcohol craving and rate of responding and decreased the number of changeovers between alcohol versus money reinforcers on the PR schedule. There was a positive relationship between alcohol craving and drinks earned during the stress session. This novel paradigm provides an experimental platform to examine motivation to drink without confounding by actual alcohol ingestion during the work session, thereby setting the stage for future studies of alcohol interventions.This study developed an alcohol-motivated response (AMR) procedure to examine effects of psychosocial stress on alcohol craving and several operant behaviors in persons with alcohol use disorder. Following the Trier Psychosocial Stress Test, there was a positive relationship between alcohol craving and drinks earned during the AMR session. This novel paradigm provides an experimental platform to examine motivation to drink without confounding by actual alcohol ingestion during the work session, setting the stage for future studies of alcohol interventions.
      PubDate: 2017-04-17T01:20:57.990613-05:
      DOI: 10.1111/adb.12511
  • The involuntary nature of binge drinking: goal directedness and awareness
           of intention
    • Authors: Nuria Doñamayor; Daniela Strelchuk, Kwangyeol Baek, Paula Banca, Valerie Voon
      Abstract: Binge drinking represents a public health issue and is a known risk factor in the development of alcohol use disorders. Previous studies have shown behavioural as well as neuroanatomical alterations associated with binge drinking. Here, we address the question of the automaticity or involuntary nature of the behaviour by assessing goal-directed behaviour and intentionality. In this study, we used a computational two-step task, designed to discern between model-based/goal-directed and model-free/habitual behaviours, and the classic Libet clock task, to study intention awareness, in a sample of 31 severe binge drinkers (BD) and 35 matched healthy volunteers. We observed that BD had impaired goal-directed behaviour in the two-step task compared with healthy volunteers. In the Libet clock task, BD showed delayed intention awareness. Further, we demonstrated that alcohol use severity, as reflected by the alcohol use disorders identification test, correlated with decreased conscious awareness of volitional intention in BD, although it was unrelated to performance on the two-step task. However, the time elapsed since the last drinking binge influenced the model-free scores, with BD showing less habitual behaviour after longer abstinence. Our findings suggest that the implementation of goal-directed strategies and the awareness of volitional intention are affected in current heavy alcohol users. However, the modulation of these impairments by alcohol use severity and abstinence suggests a state effect of alcohol use in these measures and that top-down volitional control might be ameliorated with alcohol use cessation.Model-based/goal-directed and model-free/habitual behaviours and intention awareness were assessed in 31 severe binge drinkers and 35 healthy volunteers. Binge drinkers showed impaired goal-directed behaviour and delayed intention awareness. Further, alcohol use severity correlated with decreased intention awareness, and the time elapsed since the last drinking binge influenced goal-directed and habitual behaviours. This modulation suggests a state effect of alcohol use in these measures and that top-down volitional control might be ameliorated with alcohol use cessation.
      PubDate: 2017-04-16T23:20:33.033353-05:
      DOI: 10.1111/adb.12505
  • Adolescents' behavioral and neural responses to e-cigarette advertising
    • Authors: Yvonnes Chen; Carina H. Fowler, Vlad B. Papa, Rebecca J. Lepping, Morgan G. Brucks, Andrew T. Fox, Laura E. Martin
      Abstract: Although adolescents are a group heavily targeted by the e-cigarette industry, research in cue-reactivity has not previously examined adolescents' behavioral and neural responses to e-cigarette advertising. This study addressed this gap through two experiments. In Experiment One, adult traditional cigarette smokers (n = 41) and non-smokers (n = 41) answered questions about e-cigarette and neutral advertising images. The 40 e-cigarette advertising images that most increased desire to use the product were matched to 40 neutral advertising images with similar content. In Experiment Two, the 80 advertising images selected in Experiment One were presented to adolescents (n = 30) during an functional magnetic resonance imaging brain scan. There was a range of traditional cigarette smoking across the sample with some adolescents engaging in daily smoking and others who had never smoked. Adolescents self-reported that viewing the e-cigarette advertising images increased their desire to smoke. Additionally, all participants regardless of smoking statuses showed significantly greater brain activation to e-cigarette advertisements in areas associated with cognitive control (left middle frontal gyrus), reward (right medial frontal gyrus), visual processing/attention (left lingual gyrus/fusiform gyrus, right inferior parietal lobule, left posterior cingulate, left angular gyrus) and memory (right parahippocampus, left insula). Further, an exploratory analysis showed that compared with age-matched non-smokers (n = 7), adolescent smokers (n = 7) displayed significantly greater neural activation to e-cigarette advertising images in the left inferior temporal gyrus/fusiform gyrus, compared with their responses to neutral advertising images. Overall, participants' brain responses to e-cigarette advertisements suggest a need to further investigate the long-run impact of e-cigarette advertising on adolescents.Adolescents (n = 30) with various smoking experiences (non-smokers to daily smokers) self-reported that viewing the e-cigarette advertisements increased their desire to smoke. They also showed significantly greater brain activation to e-cigarette advertisements in areas associated with cognitive control, reward, visual processing/attention, and memory. Further, an exploratory analysis showed that compared to age-matched non-smokers (n = 7), adolescent smokers (n = 7) displayed significantly greater neural activation to e-cigarette advertising images in the left inferior temporal gyrus/fusiform gyrus, compared to their responses to neutral advertising images.
      PubDate: 2017-04-11T23:20:35.911987-05:
      DOI: 10.1111/adb.12510
  • Intra-prelimbic cortical inhibition of striatal-enriched tyrosine
           phosphatase suppresses cocaine seeking in rats
    • Authors: Ben M. Siemsen; Paul J. Lombroso, Jacqueline F. McGinty
      Abstract: Cocaine self-administration in rats results in dysfunctional neuroadaptations in the prelimbic (PrL) cortex during early abstinence. Central to these adaptations is decreased phospho-extracellular signal-regulated kinase (p-ERK), which plays a key role in cocaine seeking. Normalizing ERK phosphorylation in the PrL cortex immediately after cocaine self-administration decreases subsequent cocaine seeking. The disturbance in ERK phosphorylation is accompanied by decreased phosphorylation of striatal-enriched protein tyrosine phosphatase (STEP), indicating increased STEP activity. STEP is a well-recognized ERK phosphatase but whether STEP activation during early abstinence mediates the decrease in p-ERK and is involved in relapse is unknown. Here, we show that a single intra-PrL cortical microinfusion of the selective STEP inhibitor, TC-2153, immediately after self-administration suppressed post-abstinence context-induced relapse under extinction conditions and cue-induced reinstatement, but not cocaine prime-induced drug seeking or sucrose seeking. Moreover, an intra-PrL cortical TC-2153 microinfusion immediately after self-administration prevented the cocaine-induced decrease in p-ERK within the PrL cortex during early abstinence. Interestingly, a systemic TC-2153 injection at the same timepoint failed to suppress post-abstinence context-induced relapse or cue-induced reinstatement, but did suppress cocaine prime-induced reinstatement. These data indicate that the STEP-induced ERK dephosphorylation in the PrL cortex during early abstinence is a critical neuroadaptation that promotes relapse to cocaine seeking and that systemic versus intra-PrL cortical inhibition of STEP during early abstinence differentially suppresses cocaine seeking.Intra-prelimbic cortical inhibition of striatal-enriched protein tyrosine phosphatase with the relatively selective inhibitor, TC-2153, immediately following cocaine self-administration prevents the critical extracellular signal-regulated kinase dephosphorylation within the prelimbic cortex during early abstinence and also prevents subsequent relapse to cocaine seeking following abstinence and extinction training.
      PubDate: 2017-03-28T01:15:38.015995-05:
      DOI: 10.1111/adb.12504
  • Acupuncture reduces relapse to cocaine-seeking behavior via activation of
           GABA neurons in the ventral tegmental area
    • Authors: Wyju Jin; Min Sun Kim, Eun Young Jang, Jun Yeon Lee, Jin Gyeom Lee, Hong Yu Kim, Seong Shoon Yoon, Bong Hyo Lee, Suchan Chang, Jae Hyo Kim, Kwang H. Choi, Ho Koo, Young Seob Gwak, Scott C. Steffensen, Yeon-Hee Ryu, Hee Young Kim, Chae Ha Yang
      Abstract: There is growing public interest in alternative approaches to addiction treatment and scientific interest in elucidating the neurobiological underpinnings of acupuncture. Our previous studies showed that acupuncture at a specific Shenmen (HT7) points reduced dopamine (DA) release in the nucleus accumbens (NAc) induced by drugs of abuse. The present study was carried out to evaluate the effects of HT7 acupuncture on γ-aminobutyric acid (GABA) neuronal activity in the ventral tegmental area (VTA) and the reinstatement of cocaine-seeking behavior. Using microdialysis and in vivo single-unit electrophysiology, we evaluated the effects of HT7 acupuncture on VTA GABA and NAc DA release and VTA GABA neuronal activity in rats. Using a within-session reinstatement paradigm in rats self-administering cocaine, we evaluated the effects of HT7 stimulation on cocaine-primed reinstatement. Acupuncture at HT7 significantly reduced cocaine suppression of GABA release and GABA neuron firing rates in the VTA. HT7 acupuncture attenuated cocaine-primed reinstatement, which was blocked by VTA infusions of the selective GABAB receptor antagonist 2-hydroxysaclofen. HT7 stimulation significantly decreased acute cocaine-induced DA release in the NAc, which was also blocked by 2-hydroxysaclofen. HT7 acupuncture also attenuated cocaine-induced sensitization of extracellular DA levels in the NAc. Moreover, HT7 acupuncture reduced both locomotor activity and neuronal activation in the NAc induced by acute cocaine in a needle-penetration depth-dependent fashion. These results suggest that acupuncture may suppress cocaine-induced DA release in the NAc and cocaine-seeking behavior through activation of VTA GABA neurons. Acupuncture may be an effective therapy to reduce cocaine relapse by enhancing GABAergic inhibition in the VTA.We provide Figure b as a suitable figure. We also summarized 3 sentences from our findings.HT7 acupuncture significantly reduced cocaine suppression of γ-aminobutyric acid (GABA) release and GABA neuron firing rates in the ventral tegmental area.HT7 acupuncture attenuated cocaine-primed reinstatement and cocaine-induced sensitization of extracellular dopamine levels in the nucleus accumbens, which are blocked by GABAB receptor antagonist 2-hydroxysaclofen.HT7 acupuncture reduced both locomotor activity and neuronal activation in the nucleus accumbens induced by acute cocaine in a needle-penetration depth-dependent fashion.
      PubDate: 2017-03-07T20:15:43.14704-05:0
      DOI: 10.1111/adb.12499
  • Naltrexone ameliorates functional network abnormalities in
           alcohol-dependent individuals
    • Authors: Laurel S. Morris; Kwangyeol Baek, Roger Tait, Rebecca Elliott, Karen D. Ersche, Remy Flechais, John McGonigle, Anna Murphy, Liam J. Nestor, Csaba Orban, Filippo Passetti, Louise M. Paterson, Ilan Rabiner, Laurence Reed, Dana Smith, John Suckling, Eleanor M. Taylor, Edward T. Bullmore, Anne R. Lingford-Hughes, Bill Deakin, David J. Nutt, Barbara J. Sahakian, Trevor W. Robbins, Valerie Voon,
      Abstract: Naltrexone, an opioid receptor antagonist, is commonly used as a relapse prevention medication in alcohol and opiate addiction, but its efficacy and the mechanisms underpinning its clinical usefulness are not well characterized. In the current study, we examined the effects of 50-mg naltrexone compared with placebo on neural network changes associated with substance dependence in 21 alcohol and 36 poly-drug-dependent individuals compared with 36 healthy volunteers. Graph theoretic and network-based statistical analysis of resting-state functional magnetic resonance imaging (MRI) data revealed that alcohol-dependent subjects had reduced functional connectivity of a dispersed network compared with both poly-drug-dependent and healthy subjects. Higher local efficiency was observed in both patient groups, indicating clustered and segregated network topology and information processing. Naltrexone normalized heightened local efficiency of the neural network in alcohol-dependent individuals, to the same levels as healthy volunteers. Naltrexone failed to have an effect on the local efficiency in abstinent poly-substance-dependent individuals. Across groups, local efficiency was associated with substance, but no alcohol exposure implicating local efficiency as a potential premorbid risk factor in alcohol use disorders that can be ameliorated by naltrexone. These findings suggest one possible mechanism for the clinical effects of naltrexone, namely, the amelioration of disrupted network topology.Neural network characteristics were assessed in alcohol-dependent and poly-substance-dependent individuals. Both groups displayed disturbed network topology, suggesting clustered and segregated information processing. A single 50-mg dose of naltrexone, an opioid receptor antagonist commonly used as a relapse prevention medication in addiction, normalized the aberrant neural network organization (local efficiency) in alcohol-dependent and not poly-substance-dependent individuals. These findings suggest that the clinical effects of naltrexone in alcohol-dependent individuals might relate to an amelioration of disrupted network topology.
      PubDate: 2017-02-28T21:55:32.609313-05:
      DOI: 10.1111/adb.12503
  • On the relationships in rhesus macaques between chronic ethanol
           consumption and the brain transcriptome
    • Authors: Ovidiu D. Iancu; Alexander Colville, Nicole A.R. Walter, Priscila Darakjian, Denesa L. Oberbeck, James B. Daunais, Christina L. Zheng, Robert P. Searles, Shannon K. McWeeney, Kathleen A. Grant, Robert Hitzemann
      Abstract: This is the first description of the relationship between chronic ethanol self-administration and the brain transcriptome in a non-human primate (rhesus macaque). Thirty-one male animals self-administered ethanol on a daily basis for over 12 months. Gene transcription was quantified with RNA-Seq in the central nucleus of the amygdala (CeA) and cortical Area 32. We constructed coexpression and cosplicing networks, and we identified areas of preservation and areas of differentiation between regions and network types. Correlations between intake and transcription included largely distinct gene sets and annotation categories across brain regions and between expression and splicing; positive and negative correlations were also associated with distinct annotation groups. Membrane, synaptic and splicing annotation categories were over-represented in the modules (gene clusters) enriched in positive correlations (CeA); our cosplicing analysis further identified the genes affected only at the exon inclusion level. In the CeA coexpression network, we identified Rab6b, Cdk18 and Igsf21 among the intake-correlated hubs, while in the Area 32, we identified a distinct hub set that included Ppp3r1 and Myeov2. Overall, the data illustrate that excessive ethanol self-administration is associated with broad expression and splicing mechanisms that involve membrane and synapse genes.Four cohorts of male rhesus monkeys (n = 32) followed a protocol of>12 months of chronic alcohol self-administration. Analyzing the brain transcriptome in amygdala and cortical area 32 via RNA-Seq revealed coexpression and cosplicing networks that are unique to each other and unique to brain region. Specifically, coexpression modules enriched in genes correlated to alcohol intake reveal increased expression of membrane and synaptic genes and decreased expression of translational genes in amygdala.
      PubDate: 2017-02-28T21:50:28.81123-05:0
      DOI: 10.1111/adb.12501
  • In vivo structural imaging in rats reveals neuroanatomical correlates of
           behavioral sub-dimensions of cocaine addiction
    • Authors: Nazzareno Cannella; Alejandro Cosa-Linan, Elena Büchler, Claudia Falfan-Melgoza, Wolfgang Weber-Fahr, Rainer Spanagel
      Abstract: Cocaine addiction is a multi-dimensional behavioral disorder characterized by a loss of control over cocaine taking despite of detrimental consequences. Structural MRI studies have revealed association between cocaine consumption and gray matter volume (GMV) in cocaine-addicted patients. However, the behavioral correlates of GMV in cocaine addiction are poorly understood. Here, we used a DSM-IV-based rat model of cocaine addiction with high face validity for structural imaging. According to three behavioral sub-dimensions of addiction, rats were separated into two groups showing either addict-like or non-addict-like behavior. These behavioral sub-dimensions were (1) the inability to refrain from drug-seeking and taking, (2) high motivation for the drug, and (3) maintained drug use despite negative consequences. In these rats, we performed structural MRI with voxel-based morphometry and analyzed the interaction of GMV with behavioral sub-dimensions in cocaine-addicted rats. Our major findings are that GMV differentially correlate with the inability to refrain from drug-seeking and taking in addict-like and non-addict-like rats within the somatosensory cortices and the amygdala. High motivation for the drug differentially correlates with GMV in addict-like and non-addict-like rats within the medial prefrontal cortex, and maintained drug use despite negative consequences differentially correlates with GMV in these two groups of rats within the periaqueductal gray. Our results demonstrate that the behavioral differences characterizing addict-like and non-addict-like rats in each behavioral sub-dimension of addiction are reflected by divergent covariance with GMV. We conclude that structural imaging provides specific neuroanatomical correlates of behavioral sub-dimensions of addiction.Enhanced somatosensory and insular cortex gray matter volume (GMV) predicts perseverance in cocaine seeking. Lower medial prefontal cortex GMV predicts enhanced motivation for cocaine. Lower PAG periaqueductal gray GMV predicts enhanced compulsivity in addicted rats.
      PubDate: 2017-02-23T19:30:45.295146-05:
      DOI: 10.1111/adb.12500
  • Default mode network deactivation to smoking cue relative to food cue
           predicts treatment outcome in nicotine use disorder
    • Authors: Claire E. Wilcox; Eric D. Claus, Vince D. Calhoun, Srinivas Rachakonda, Rae A. Littlewood, Jessica Mickey, Pamela B. Arenella, Natalie Goodreau, Kent E. Hutchison
      Abstract: Identifying predictors of treatment outcome for nicotine use disorders (NUDs) may help improve efficacy of established treatments, like varenicline. Brain reactivity to drug stimuli predicts relapse risk in nicotine and other substance use disorders in some studies. Activity in the default mode network (DMN) is affected by drug cues and other palatable cues, but its clinical significance is unclear. In this study, 143 individuals with NUD (male n = 91, ages 18–55 years) received a functional magnetic resonance imaging scan during a visual cue task during which they were presented with a series of smoking-related or food-related video clips prior to randomization to treatment with varenicline (n = 80) or placebo. Group independent components analysis was utilized to isolate the DMN, and temporal sorting was used to calculate the difference between the DMN blood-oxygen-level dependent signal during smoke cues and that during food cues for each individual. Food cues were associated with greater deactivation compared with smoke cues in the DMN. In correcting for baseline smoking and other clinical variables, which have been shown to be related to treatment outcome in previous work, a less positive Smoke − Food difference score predicted greater smoking at 6 and 12 weeks when both treatment groups were combined (P = 0.005, β = −0.766). An exploratory analysis of executive control and salience networks demonstrated that a more positive Smoke − Food difference score for executive control network predicted a more robust response to varenicline relative to placebo. These findings provide further support to theories that brain reactivity to palatable cues, and in particular in DMN, may have a direct clinical relevance in NUD.One hundred forty-three individuals with nicotine use disorder underwent a visual cue task during functional MRI that involved exposure to smoking (Smoke) and food (Food) cue videos, before undergoing treatment (varenicline or placebo). Greater deactivation to Food relative to Smoke was observed in the default mode network, and a less positive Smoke–Food difference score predicted worse treatment outcomes, combining both treatment groups. A more positive Smoke–Food difference score in executive control network predicted a better response to varenicline relative to placebo.
      PubDate: 2017-02-23T19:30:32.868548-05:
      DOI: 10.1111/adb.12498
  • Polygenic risk scores for schizophrenia and bipolar disorder associate
           with addiction
    • Authors: Gunnar W. Reginsson; Andres Ingason, Jack Euesden, Gyda Bjornsdottir, Sigurgeir Olafsson, Engilbert Sigurdsson, Hogni Oskarsson, Thorarinn Tyrfingsson, Valgerdur Runarsdottir, Ingunn Hansdottir, Stacy Steinberg, Hreinn Stefansson, Daniel F. Gudbjartsson, Thorgeir E. Thorgeirsson, Kari Stefansson
      Abstract: We use polygenic risk scores (PRSs) for schizophrenia (SCZ) and bipolar disorder (BPD) to predict smoking, and addiction to nicotine, alcohol or drugs in individuals not diagnosed with psychotic disorders. Using PRSs for 144 609 subjects, including 10 036 individuals admitted for in-patient addiction treatment and 35 754 smokers, we find that diagnoses of various substance use disorders and smoking associate strongly with PRSs for SCZ (P = 5.3 × 10−50–1.4 × 10−6) and BPD (P = 1.7 × 10−9–1.9 × 10−3), showing shared genetic etiology between psychosis and addiction. Using standardized scores for SCZ and BPD scaled to a unit increase doubling the risk of the corresponding disorder, the odds ratios for alcohol and substance use disorders range from 1.19 to 1.31 for the SCZ-PRS, and from 1.07 to 1.29 for the BPD-PRS. Furthermore, we show that as regular smoking becomes more stigmatized and less prevalent, these biological risk factors gain importance as determinants of the behavior.Using polygenic risk scores (PRSs) for schizophrenia (SCZ) and bipolar disorder (BPD) to predict smoking behavior and alcohol or drug addiction in 144,609 subjects, we find that smoking and diagnoses of various substance use disorders associate strongly with PRSs for SCZ (P = 5.3 × 10−50–1.4 × 10−6) and BPD (P = 1.7 × 10−9–1.9 × 10−3). Furthermore, we show that the impact of SCZ-PRS on smoking is rising with time, increasingly casting regular smoking as a psychiatric condition sharing genetic risk with SCZ and BPD.
      PubDate: 2017-02-23T19:30:26.066257-05:
      DOI: 10.1111/adb.12496
  • Addiction research and theory: a commentary on the Surgeon General's
           Report on alcohol, drugs, and health
    • Authors: Aldo Badiani; Kent C. Berridge, Markus Heilig, David J. Nutt, Terry E. Robinson
      Abstract: The Office of the Surgeon General recently produced its first Report on the consequences of alcohol and drug abuse on health, making several very laudable policy recommendations. The Report also emphasizes the importance of adequate funding for biomedical research, which is good news for both researchers and patients. However, the Report is marred by a biased viewpoint on the psychology and neurobiology of drug addiction. We highlight here four controversial issues that were depicted as facts in the Report, thereby potentially misleading non-expert readers about the current state-of-the-art understanding of the psychology and neurobiology of drug addiction. It will be important to recognize a fuller range of scientific viewpoints in addiction neuroscience to avoid amplifying this bias in the coming years.
      PubDate: 2017-02-21T23:55:50.03144-05:0
      DOI: 10.1111/adb.12497
  • Modeling human methamphetamine use patterns in mice: chronic and binge
           methamphetamine exposure, reward function and neurochemistry
    • Authors: James P. Kesby; Ariel Chang, Athina Markou, Svetlana Semenova
      Abstract: Different methamphetamine use patterns in human subjects may contribute to inconsistent findings regarding the effects of methamphetamine abuse on brain and behavior. The present study investigated whether human-derived chronic and binge methamphetamine use patterns have differential effects on reward and neurochemistry in mice. Brain reward function in mice was evaluated during acute/prolonged withdrawal, and in response to methamphetamine challenge using the intracranial self-stimulation procedure. Brain dopaminergic, serotonergic and glutamatergic neurochemistry was determined with high-performance liquid chromatography. Chronic and binge regimens induced withdrawal-related decreases in reward function that were more severe during the binge regimen during cycles 1–2. Despite large differences in methamphetamine dose, both regimens induced similar reward deficits during cycles 3–4. Neither methamphetamine regimen led to persistent alterations in the sensitivity to the reward-enhancing effects of acute methamphetamine challenge. The binge regimen severely depleted striatal dopamine levels and increased brain glutamine levels. The chronic regimen had milder effects on striatal dopamine levels and altered cortical dopamine and serotonin levels. This work highlights that the magnitude of acute/prolonged withdrawal may not reflect amount or frequency of methamphetamine intake. In contrast, the array of underlying neurochemical alterations was methamphetamine regimen dependent. Thus, stratifying methamphetamine-dependent individuals based on use pattern may help to cater therapeutic interventions more appropriately by targeting use pattern-specific neurotransmitter systems.We examined human-derived binge and chronic methamphetamine use patterns in mice. Both regimens induced a similar magnitude of reward deficits during withdrawal and methamphetamine-challenge-induced reward enhancement. The binge regimen depleted dopamine levels in the striatum and increased glutamine levels throughout the brain. The chronic regimen moderately decreased dopamine levels in the striatum and altered cortical dopamine and serotonin levels. This study demonstrates that aspects of reward and neurochemistry can be either independent or dependent on methamphetamine use parameters.
      PubDate: 2017-02-21T23:55:45.823826-05:
      DOI: 10.1111/adb.12502
  • Cannabidiol reduces ethanol consumption, motivation and relapse in mice
    • Authors: Adrián Viudez-Martínez; María S. García-Gutiérrez, Carmen María Navarrón, María Isabel Morales-Calero, Francisco Navarrete, Ana Isabel Torres-Suárez, Jorge Manzanares
      Abstract: This study evaluated the effects of cannabidiol (CBD) on ethanol reinforcement, motivation and relapse in C57BL/6 J mice. The effects of CBD (60 mg/kg, i.p.) on blood ethanol concentration, hypothermia and handling-induced convulsions associated to acute ethanol administration were evaluated. The two-bottle choice paradigm was performed to assess the effects of CBD (30, 60 and 120 mg/kg/day, i.p.) on ethanol intake and preference. In addition, an oral ethanol self-administration experiment was carried out to evaluate the effects of CBD [a single s.c. administration of a microparticle formulation providing CBD continuous controlled release (30 mg/kg/day)] on the reinforcement and motivation for ethanol. The effects of CBD (60 and 120 mg/kg/day, i.p.) on ethanol-induced relapse were also evaluated. Gene expression analyses of tyrosine hydroxylase in ventral tegmental area and μ-opioid (Oprm1), cannabinoid (CB1r and CB2r) and GPR55 receptors in nucleus accumbens (NAcc) were carried out by real-time polymerase chain reaction.Cannabidiol reduced the ethanol-induced hypothermia and handling-induced convulsion but failed to modify blood ethanol concentration. CBD reduced ethanol consumption and preference in the two-bottle choice, significantly decreased ethanol intake and the number of effective responses in the oral ethanol self-administration, and reduced ethanol-induced relapse. Furthermore, the administration of CBD significantly reduced relative gene expression of tyrosine hydroxylase in the ventral tegmental area, Oprm1, CB1r and GPR55 in the NAcc and significantly increased CB2r in the NAcc.Taken together, these results reveal that the administration of CBD reduced the reinforcing properties, motivation and relapse for ethanol. These findings strongly suggest that CBD may result useful for the treatment of alcohol use disorders.The present study strongly points out that cannabidiol (CBD) reduced the reinforcing and motivational properties of ethanol and prevented ethanol-induced relapse. These behavioral alterations are associated with alterations in key targets closely related with alcohol addiction (Oprm-1, TH, CB1r, CB2r and GPR55). In conclusion, the results suggest that CBD deserves further exploration as a potential therapeutic drug for the treatment of alcohol use disorders (AUD).
      PubDate: 2017-02-13T21:15:47.063112-05:
      DOI: 10.1111/adb.12495
  • Gray-matter relationships to diagnostic and transdiagnostic features of
           drug and behavioral addictions
    • Authors: Sarah W. Yip; Patrick D. Worhunsky, Jiansong Xu, Kristen P. Morie, R. Todd Constable, Robert T. Malison, Kathleen M. Carroll, Marc N. Potenza
      Abstract: Alterations in neural structure have been reported in both cocaine-use disorder and gambling disorder, separately, suggesting similarities across addiction diagnoses. Individual variation in neural structure has also been associated with impulsivity, a dimensional construct implicated in addictions. This study combines categorical (diagnosis-based) and dimensional (transdiagnostic) approaches to identify neural structural alterations linked to addiction subtypes and trait impulsivity, respectively, across individuals with gambling disorder (n = 35), individuals with cocaine-use disorder (n = 37) and healthy comparison individuals (n = 37). High-resolution T1-weighted data were analyzed using modulated voxel-based morphometry (VBM). Statistical analyses were conducted using whole-brain general-linear models, corrected for family-wise error (pFWE 
      PubDate: 2017-02-01T20:10:45.68669-05:0
      DOI: 10.1111/adb.12492
  • Bidirectional relationship between alcohol intake and sensitivity to
           social defeat: association with Tacr1 and Avp expression
    • Authors: Britta S. Nelson; Michelle K. Sequeira, Jesse R. Schank
      Abstract: While epidemiological studies show that alcohol abuse is often co-morbid with affective disorders, the causal direction of this association is unclear. We examined this relationship using mouse models including social defeat stress (SDS), social interaction (SI) and voluntary alcohol consumption. C57BL6/J mice exposed to SDS segregate into two subpopulations, those that express depressive-like phenotypes (‘susceptible’) and those that do not (‘resilient’). First, we stratified SDS-exposed mice and measured their voluntary alcohol consumption. Next, we determined whether SI behavior in alcohol-naïve mice could predict alcohol intake. Finally, we assessed the effect of binge-like alcohol exposure on sensitivity to SDS. We quantified Tacr1 (neurokinin-1 receptor gene) and Avp (vasopressin peptide gene) mRNA in brain regions involved in depression, addiction and social behavior. We found that susceptible mice consumed more alcohol compared with resilient mice, suggesting that depression-like phenotypes associate with increased alcohol intake. Interestingly, we observed a negative correlation between SI and alcohol intake in stress- and alcohol-naïve mice, suggesting that individual differences in SI associate with alcohol preference. Finally, alcohol pre-treatment increased sensitivity to SDS, indicating that alcohol exposure alters sensitivity to social stress. Quantification of mRNA revealed that increased expression of Tacr1 and Avp generally associated with decreased SI and increased alcohol intake. C57BL6/J mice are an inbred strain; thus, it is likely that individual differences in behavior and gene expression are driven by epigenetic factors. Collectively, these results support a bidirectional relationship between alcohol exposure and susceptibility to stress that is associated with variations in neuropeptide expression.Although the comorbidity between alcoholism and depression is well established, the degree to which either condition precedes or affects the other is unknown. We used preclinical models to elucidate potential behavioral and molecular interactions between these two conditions. Our findings support a bidirectional relationship, with the onset on one condition increasing the risk of the other as well as identifying NK1R and AVP expression as factors involved in increased susceptibility for depressive and addictive behaviors.
      PubDate: 2017-02-01T20:10:39.297037-05:
      DOI: 10.1111/adb.12494
  • Severity of alcohol dependence is associated with the fatty acid amide
           hydrolase Pro129Thr missense variant
    • Authors: Matthew E. Sloan; Joshua L. Gowin, Jia Yan, Melanie L. Schwandt, Primavera A. Spagnolo, Hui Sun, Colin A. Hodgkinson, David Goldman, Vijay A. Ramchandani
      Abstract: The endocannabinoid system plays an important role in reward and addiction. One of the two main endocannabinoid neurotransmitters, anandamide, is metabolized by fatty acid amide hydrolase, an enzyme with a functional genetic polymorphism (FAAH Pro129Thr, rs324420). The Thr129 allele has been linked to problem drug and alcohol use, but the association has not been widely replicated and may be stronger for clinical measures of severity rather than categorical diagnosis. In the present study, we sought to determine whether the Thr129 allele was associated with both alcohol dependence (AD) diagnosis and severity in a sample of 1434 European American and African American individuals, 952 of whom were diagnosed with lifetime AD. Participants were genotyped for FAAH rs324420, and ancestry was determined via a genome-wide panel of ancestry informative markers. Subjects participated in Structured Clinical Interviews for psychiatric disorders and 90-day Timeline Followback interviews to assess recent alcohol use. European American participants with current AD had a higher Thr129 allele frequency than non-dependent controls. In European Americans with lifetime AD, there were significantly different distributions of drinking days and binge drinking days between the two genotype groups, with Thr129 carriers reporting a median of 10 fewer abstinent days and 13 more binge drinking days than Pro129/Pro129 homozygotes. In African American participants, there were no significant differences between Thr129 allele frequency in cases and controls and no significant differences in measures of AD severity by genotype. These findings provide evidence that the Pro129Thr missense variant is associated with AD severity in European Americans.The endocannabinoid system modulates brain reward signaling and is thought to influence addictive behaviors. We investigated whether a functional polymorphism in the fatty acid amide hydrolase (FAAH) gene, which encodes an enzyme responsible for metabolizing the endocannabinoid neurotransmitter anandamide, is associated with both risk and severity of alcohol dependence. European American Thr129 allele carriers had higher odds of a current diagnosis of alcohol dependence compared to non-dependent controls (OR = 1.35, 95% CI 1.05 to 1.74) after controlling for covariates. European American alcohol dependent Thr129 carriers reported a median of 10 fewer abstinence days and 13 more binge drinking days during a 90-day recall period than Pro129/Pro129 homozygotes. These findings suggest that endocannabinoid signaling may play an important role in human alcohol consumption.
      PubDate: 2017-02-01T20:05:40.29517-05:0
      DOI: 10.1111/adb.12491
  • Whole genome sequence study of cannabis dependence in two independent
    • Authors: Ian R. Gizer; Chris Bizon, David A. Gilder, Cindy L. Ehlers, Kirk C. Wilhelmsen
      Abstract: Recent advances in genome wide sequencing techniques and analytical methods allow for more comprehensive examinations of the genome than microarray-based genome-wide association studies (GWAS). The present report provides the first application of whole genome sequencing (WGS) to identify low frequency variants involved in cannabis dependence across two independent cohorts. The present study used low-coverage whole genome sequence data to conduct set-based association and enrichment analyses of low frequency variation in protein-coding regions as well as regulatory regions in relation to cannabis dependence. Two cohorts were studied: a population-based Native American tribal community consisting of 697 participants nested within large multi-generational pedigrees and a family-based sample of 1832 predominantly European ancestry participants largely nested within nuclear families. Participants in both samples were assessed for Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) lifetime cannabis dependence, with 168 and 241 participants receiving a positive diagnosis in each sample, respectively. Sequence kernel association tests identified one protein-coding region, C1orf110 and one regulatory region in the MEF2B gene that achieved significance in a meta-analysis of both samples. A regulatory region within the PCCB gene, a gene previously associated with schizophrenia, exhibited a suggestive association. Finally, a significant enrichment of regions within or near genes with multiple splice variants or involved in cell adhesion or potassium channel activity were associated with cannabis dependence. This initial study demonstrates the potential utility of low pass whole genome sequencing for identifying genetic variants involved in the etiology of cannabis use disorders.The present study used low-coverage whole genome sequence data to conduct set-based association analyses of low frequency variation in protein-coding regions as well as regulatory regions in relation to cannabis dependence. Sequence kernel association tests identified one protein-coding region, C1orf110, and one regulatory region in the MEF2B gene that achieved significance in a meta-analysis of both samples. The MEF2B regulatory element was characterized by H3K9me3 and H3K36me histone marks, suggesting it may be important for protecting exons from recombination and regulation of alternative splicing.
      PubDate: 2017-01-23T03:05:30.26811-05:0
      DOI: 10.1111/adb.12489
  • No association of goal-directed and habitual control with alcohol
           consumption in young adults
    • Authors: Stephan Nebe; Nils B. Kroemer, Daniel J. Schad, Nadine Bernhardt, Miriam Sebold, Dirk K. Müller, Lucie Scholl, Sören Kuitunen-Paul, Andreas Heinz, Michael A. Rapp, Quentin J.M. Huys, Michael N. Smolka
      Abstract: Alcohol dependence is a mental disorder that has been associated with an imbalance in behavioral control favoring model-free habitual over model-based goal-directed strategies. It is as yet unknown, however, whether such an imbalance reflects a predisposing vulnerability or results as a consequence of repeated and/or excessive alcohol exposure. We, therefore, examined the association of alcohol consumption with model-based goal-directed and model-free habitual control in 188 18-year-old social drinkers in a two-step sequential decision-making task while undergoing functional magnetic resonance imaging before prolonged alcohol misuse could have led to severe neurobiological adaptations. Behaviorally, participants showed a mixture of model-free and model-based decision-making as observed previously. Measures of impulsivity were positively related to alcohol consumption. In contrast, neither model-free nor model-based decision weights nor the trade-off between them were associated with alcohol consumption. There were also no significant associations between alcohol consumption and neural correlates of model-free or model-based decision quantities in either ventral striatum or ventromedial prefrontal cortex. Exploratory whole-brain functional magnetic resonance imaging analyses with a lenient threshold revealed early onset of drinking to be associated with an enhanced representation of model-free reward prediction errors in the posterior putamen. These results suggest that an imbalance between model-based goal-directed and model-free habitual control might rather not be a trait marker of alcohol intake per se.There is no association between behavioral control during a sequential decision-making task, and fMRI BOLD correlates thereof with alcohol consumption in 188 young social-drinking adults.
      PubDate: 2017-01-23T02:30:32.382068-05:
      DOI: 10.1111/adb.12490
  • Binge drinking differentially affects cortical and subcortical
    • Authors: Laurel S. Morris; Nicholas G. Dowell, Mara Cercignani, Neil A. Harrison, Valerie Voon
      Abstract: Young adult binge drinkers represent a model for endophenotypic risk factors for alcohol misuse and early exposure to repeated binge cycles. Chronic or harmful alcohol use leads to neurochemical, structural and morphological neuroplastic changes, particularly in regions associated with reward processing and motivation. We investigated neural microstructure in 28 binge drinkers compared with 38 matched healthy controls. We used a recently developed diffusion magnetic resonance imaging acquisition and analysis, which uses three-compartment modelling (of intracellular, extracellular and cerebrospinal fluid) to determine brain tissue microstructure features including neurite density and orientation dispersion index (ODI). Binge drinkers had reduced ODI, a proxy of neurite complexity, in frontal cortical grey matter and increased ODI in parietal grey matter. Neurite density was higher in cortical white matter in adjacent regions of lower ODI in binge drinkers. Furthermore, binge drinkers had higher ventral striatal grey matter ODI that was positively correlated with binge score. Healthy volunteers showed no such relationships. We demonstrate disturbed dendritic complexity of higher-order prefrontal and parietal regions, along with higher dendritic complexity of a subcortical region known to mediate reward-related motivation. The findings illustrate novel microstructural abnormalities that may reflect an infnce of alcohol bingeing on critical neurodevelopmental processes in an at-risk young adult group.Chronic or harmful alcohol use is associated with neuroplastic changes, particularly in regions associated with reward processing and motivation. Binge drinkers demonstrated disturbed neurite complexity in the dorsolateral prefrontal cortex and parietal regions, as measured by Neurite Orientation Dispersion and Density Imaging. Heightened neurite complexity in the ventral striatum of binge drinkers was associated with a more severe binge-like pattern of alcohol consumption. Disturbed microstructure in cortical and subcortical regions may reflect a disruption in higher-order prefrontal control systems and enhanced involvement of reward-related motivational systems.
      PubDate: 2017-01-20T00:26:49.882115-05:
      DOI: 10.1111/adb.12493
  • Biological stress indicators as risk markers for increased alcohol use
           following traumatic experiences
    • Authors: Sebastian Trautmann; Markus Muehlhan, Clemens Kirschbaum, Hans-Ulrich Wittchen, Michael Höfler, Tobias Stalder, Susann Steudte-Schmiedgen
      Abstract: Alcohol misuse is a common sequela of traumatic event experiences causing considerable morbidity and mortality. Although biological stress indicators have been identified as useful risk markers for the development of trauma-related disorders, no such biological indicators exist for the risk of increased alcohol use after trauma exposure. This is the first study to prospectively investigate the predictive value of long-term cortisol levels and acute stress reactivity for the risk of increased alcohol use following traumatic events. Male soldiers were examined before and 12 months following deployment using a standardized diagnostic interview. We analyzed the moderating role of baseline hair cortisol concentrations (HCCs, n = 153) as well as baseline salivary cortisol and alpha-amylase stress reactivity in response to a laboratory stressor (n = 145) in the association between new-onset traumatic events (according to the DSM-IV A1 criterion) and subsequent daily alcohol use. No main effects of pre-traumatic HCC or salivary stress markers on subsequent change in alcohol use were observed. However, we found that with decreasing HCC, the number of new-onset traumatic events was more strongly associated with subsequent alcohol use independent from changes in posttraumatic stress disorder symptoms. No such relation was seen for the acute stress reactivity data. Taken together, this study provides first evidence suggesting that individual differences in long-term cortisol regulation are involved in the association between traumatic experiences and subsequent alcohol use. HCC may thus serve as a potential target in the early identification of individuals vulnerable for increased alcohol use following traumatic events.We analyzed the predictive value of basal cortisol secretion [hair cortisol concentrations (HCCs)] and stress reactivity (cortisol and alpha amylase response to a laboratory stressor) for the risk of increased alcohol use following traumatic events. The number of traumatic events was related to subsequent alcohol use only in individuals with low HCC, suggesting HCC as a valuable target for potential risk markers of increased alcohol use following stressful events.
      PubDate: 2017-01-20T00:11:34.251383-05:
      DOI: 10.1111/adb.12487
  • Netrin G1: its downregulation in the nucleus accumbens of
           cocaine-conditioned mice and genetic association in human cocaine
    • Authors: Sabah Kelaï; Nicolas Ramoz, Jean-Marie Moalic, Florence Noble, Naguib Mechawar, Sandrine Imbeaud, Gustavo Turecki, Michel Simonneau, Philip Gorwood, Gilles Maussion
      Abstract: Netrin G1 is a presynaptic ligand involved in axonal projection. Although molecular mechanisms underlying cocaine addiction are still poorly understood, Netrin G1 might have a role as a regulator of anxiety, fear and spatial memory, behavioural traits impaired in the context of cocaine exposure. In this study, the Netrin G1 (Ntng1) expression was investigated in the nucleus accumbens of mice primarily conditioned to cocaine using a place preference paradigm. A genetic association study was then conducted on 146 multiplex families of the Collaborative study on Genetics of Alcoholism, in which seven single nucleotide polymorphisms located in the NTNG1 gene were genotyped. NTNG1 expression levels were also quantified in BA10, BA46 and the cerebellum of healthy controls (with no Axis 1 psychopathology). Decreased Ntng1 expression was initially observed in the nucleus accumbens of mice conditioned to cocaine. Significant genetic family-based associations were detected between NTNG1 polymorphisms and cocaine dependence. NTNG1 expression in BA10, BA46 and the cerebellum, however, were not significantly associated with any allele or haplotype of this gene. These results confirm that Ntng1 expression is disturbed in the nucleus accumbens of mice, after cocaine conditioning. A haplotype of NTNG1 was found to constitute a vulnerability factor for cocaine use disorder in patients, although none of its single nucleotide polymorphisms were associated with a differential expression pattern in healthy controls. The data suggest that change in the Ntng1 expression is a consequence of cocaine exposure, and that some of its genetic markers are associated with a greater risk for cocaine use disorder.We found a decreased Ntng1 expression in the nucleus accumbens of mice conditioned to cocaine. Furthermore, significant genetic family-based associations were detected between NTNG1 polymorphisms and cocaine dependence in 146 multiplex families of the Collaborative study on Genetics of Alcoholism. The data suggest that change in the NTNG1 expression is a consequence of cocaine exposure, and that some of its genetic markers are associated with a greater risk for cocaine use disorder.
      PubDate: 2017-01-11T02:10:31.333974-05:
      DOI: 10.1111/adb.12485
  • Low distress tolerance predicts heightened drug seeking and taking after
           extended abstinence from cocaine self-administration
    • Authors: Travis M. Moschak; Douglas R. Terry, Stacey B. Daughters, Regina M. Carelli
      Abstract: Distress tolerance (DT), defined as the ability to persist in goal-directed behavior while experiencing psychological distress, is associated with greater frequency of substance use and poor treatment outcomes. To examine a potential causal role substance use may play in DT, we developed a rodent model of DT in which rats had to press a lever within a continuously decreasing time window for reward while receiving negative feedback on failure trials. DT was defined as the time rats continued to seek reward before quitting the task. We assessed the relationship of DT with cocaine seeking/taking by measuring DT before cocaine self-administration (SA), and after 1 week and 1 month of drug abstinence. We found that DT prior to cocaine SA did not predict cocaine seeking/taking, yet DT measured after 1 month abstinence significantly predicted subsequent high levels of early session cocaine taking. Additionally, high DT measured after abstinence protected against high cocaine seeking, but this protective effect was blocked in rats with high impulsivity. Finally, while a decrease in 1 month-abstinent DT was observed following SA across treatment conditions, among cocaine-exposed rats, greater cocaine SA correlated with a steeper decrease in DT. These results show that low DT after drug abstinence is associated with heightened levels of cocaine seeking and taking behavior and that impulsivity influences this effect. Collectively, these results support the validity of our rodent DT model while extending the human literature and set the foundation for future animal studies designed to determine neural mechanisms underlying DT.Distress tolerance (DT), defined as the ability to persist in goal-directed behavior while experiencing distress, is associated with greater frequency of substance use and poor treatment outcomes. We developed a rodent model of DT and found that DT measured after cocaine abstinence significantly predicted subsequent high levels of cocaine seeking/taking and that some of these effects were moderated by impulsivity. Collectively, these results support the validity of our rodent DT model while extending the human literature.
      PubDate: 2017-01-11T02:00:41.278542-05:
      DOI: 10.1111/adb.12488
  • Issue Information
    • Pages: 579 - 580
      Abstract: No abstract is available for this article.
      PubDate: 2017-04-11T06:25:30.167132-05:
      DOI: 10.1111/adb.12453
  • Effects of drugs of abuse on the central neuropeptide Y system
    • Pages: 882 - 882
      PubDate: 2017-04-11T06:25:32.897068-05:
      DOI: 10.1111/adb.12518
  • CYP2A6 metabolism in the development of smoking behaviors in young adults
    • Authors: Emily Olfson; Joseph Bloom, Sarah Bertelsen, John P Budde, Naomi Breslau, Andrew Brooks, Robert Culverhouse, Grace Chan, Li-Shiun Chen, David Chorlian, Danielle M Dick, Howard J Edenberg, Sarah Hartz, Dorothy Hatsukami, Victor M Hesselbrock, Eric O Johnson, John R Kramer, Samuel Kuperman, Jacquelyn L Meyers, John Nurnberger, Bernice Porjesz, Nancy L Saccone, Marc A Schuckit, Jerry Stitzel, Jay A Tischfield, John P Rice, Alison Goate, Laura J Bierut
      Abstract: Cytochrome P450 2A6 (CYP2A6) encodes the enzyme responsible for the majority of nicotine metabolism. Previous studies support that slow metabolizers smoke fewer cigarettes once nicotine dependent but provide conflicting results on the role of CYP2A6 in the development of dependence. By focusing on the critical period of young adulthood, this study examines the relationship of CYP2A6 variation and smoking milestones. A total of 1209 European American young adults enrolled in the Collaborative Study on the Genetics of Alcoholism were genotyped for CYP2A6 variants to calculate a previously well-validated metric that estimates nicotine metabolism. This metric was not associated with the transition from never smoking to smoking initiation nor with the transition from initiation to daily smoking (P > 0.4). But among young adults who had become daily smokers (n = 506), decreased metabolism was associated with increased risk of nicotine dependence (P = 0.03) (defined as Fagerström Test for Nicotine Dependence score ≥4). This finding was replicated in the Collaborative Genetic Study of Nicotine Dependence with 335 young adult daily smokers (P = 0.02). Secondary meta-analysis indicated that slow metabolizers had a 53 percent increased odds (OR = 1.53, 95 percent CI 1.11–2.11, P = 0.009) of developing nicotine dependence compared with normal metabolizers. Furthermore, secondary analyses examining four-level response of time to first cigarette after waking (>60, 31–60, 6–30, ≤5 minutes) demonstrated a robust effect of the metabolism metric in Collaborative Study on the Genetics of Alcoholism (P = 0.03) and Collaborative Genetic Study of Nicotine Dependence (P = 0.004), illustrating the important role of this measure of dependence. These findings highlight the complex role of CYP2A6 variation across different developmental stages of smoking behaviors.This study links variation in a genome-wide significant gene, Cytochrome P450 2A6 (CYP2A6), with smoking behaviors in two independent young adult samples. The results demonstrate that a validated CYP2A6 metabolism metric is not associated with smoking initiation nor the development of daily use, but among young adult daily smokers, slow metabolism is associated with an elevated risk of nicotine dependence, which may be driven by time to first cigarette after waking. These findings elucidate the complex role of CYP2A6 variation in smoking behaviors.
      PubDate: 2016-12-29T01:34:28.160629-05:
      DOI: 10.1111/adb.12477
  • Heavy alcohol use in adolescence is associated with altered cortical
           activity: a combined TMS–EEG study
    • Authors: Outi Kaarre; Elisa Kallioniemi, Mervi Könönen, Tommi Tolmunen, Virve Kekkonen, Petri Kivimäki, Noora Heikkinen, Florinda Ferreri, Eila Laukkanen, Sara Määttä
      Abstract: Long-term alcohol use affects cognitive and neurophysiological functioning as well as structural brain development. Combining simultaneous electroencephalogram (EEG) recording with transcranial magnetic stimulation (TMS) enables direct, in vivo exploration of cortical excitability and assessment of effective and functional connectivity. In the central nervous system, the effects of alcohol are particularly mediated by alterations in gamma-aminobutyric acid (GABA)ergic neurotransmission, and TMS-evoked potentials (TEPs) N45 and N100 in EEG are known to reflect GABAergic function. However, no previous studies have examined the effects of long-term alcohol use in adolescence on TEPs. In this study, a total of 27 young adults with heavy alcohol use in adolescence and 25 age-matched, gender-matched and education-matched controls with little or no alcohol use participated in TMS–EEG measurements. The motor cortex (M1) was stimulated with an intensity of 90 percent of the resting motor threshold of the abductor pollicis brevis muscle. No significant differences were found in the resting motor threshold, TEP latencies or neuropsychological functioning between the groups. We observed an increase in the global mean field power in the time window of 54- to 75-millisecond post-TMS, as well as significant topographical differences in the P60 and N100 in those with a history of heavy drinking. Furthermore, there was a marked increase in the GABAergic N45 amplitude in alcohol users. These findings suggest that long-term alcohol use in adolescence, even when not meeting the diagnostic criteria for a disorder, is associated with changes in connectivity and cortical excitability.In this study, 27 young adults with heavy alcohol use in adolescence and 25 controls participated in TMS–EEG measurements. We observed a marked increase in the GABAergic N45 amplitude, as well as significant topographical differences in the P60 and N100 in those with a history of heavy drinking. These findings suggest that long-term alcohol use in adolescence, even when not meeting the diagnostic criteria for a disorder, is associated with changes in connectivity and cortical excitability.
      PubDate: 2016-12-23T03:15:27.980582-05:
      DOI: 10.1111/adb.12486
  • d-Cycloserine enhanced extinction of cocaine-induced conditioned place
           preference is attenuated in serotonin transporter knockout rats
    • Authors: Peter Karel; Francesca Calabrese, Marco Riva, Paola Brivio, Bas Van der Veen, Liesbeth Reneman, Michel Verheij, Judith Homberg
      Abstract: d-Cycloserine (DCS), a partial NMDA receptor agonist, has been proposed as a cognitive enhancer to facilitate the extinction of drug-related memories. However, it is unknown whether there are individual differences in the efficacy of DCS. Here, we set out to investigate the influence of serotonin transporter (5-HTT) genotype on DCS treatment outcome and the underlying neural mechanism. To that end, we first determined the mRNA levels of several NMDA receptor subunits and observed a reduction in NR1/NR2C receptors in the ventromedial prefrontal cortex and nucleus accumbens of 5-HTT−/− compared with 5-HTT+/+ rats. Based on this finding, we hypothesized a lower sensitivity to DCS in the 5-HTT−/− rats. To test this, rats were trained in a cocaine-induced conditioned place preference (CPP) paradigm. A significant extinction of CPP was observed in 5-HTT+/+ rats receiving 1 mg/kg i.v. DCS, while a similar effect was found in the 5-HTT−/− rats only after 5 mg/kg. Following CPP, we tested if DCS were able to reduce FosB/∆FosB protein expression, a molecular switch for cocaine-seeking behaviour. We observed an overall lower number of FosB/∆FosB positive cells in 5-HTT−/− ventromedial prefrontal cortex and amygdala and an overall effect of DCS treatment on the number of positive cells in the nucleus accumbens. In conclusion, in this study, we show that the dosing of DCS to facilitate the extinction of cocaine-seeking behaviour is, at least partially, determined by 5-HTT genotype.In the past, D-cycloserine (DCS) has been used to enhance extinction retention in laboratory animals. Here, we test if DCS is able to reduce drug seeking behavior in 5-HTT−/− rats after mRNA analysis showed a reduction in relevant NMDA receptor composition. We show that 5-HTT−/− rats need a higher dose of DCS to be able to reduce their drug-seeking behavior.
      PubDate: 2016-12-12T23:15:29.418845-05:
      DOI: 10.1111/adb.12483
  • Smokers and ex-smokers have shared differences in the neural substrates
           for potential monetary gains and losses
    • Authors: Liam J. Nestor; Ella McCabe, Jennifer Jones, Luke Clancy, Hugh Garavan
      Abstract: Despite an increased understanding of nicotine addiction, there is a scarcity of research comparing the neural correlates of non-drug reward between smokers and ex-smokers. Long-term changes in reward-related brain functioning for non-drug incentives may elucidate patterns of functioning that potentially contribute to ongoing smoking behaviour in current smokers. Similarly, examining the effects of previous chronic nicotine exposure during a period of extended abstinence may reveal whether there are neural correlates responsible for non-drug reward processing that are different from current smokers. The current study, therefore, sets out to examine the neural correlates of reward and loss anticipation, and their respective outcomes, in smokers, ex-smokers and matched controls using a monetary incentive delay task during functional magnetic resonance imaging. Here, we report that in the absence of any significant behavioural group differences, both smokers and ex-smokers showed a significantly greater activation change in the lateral orbitofrontal/anterior insular cortex compared with smokers when anticipating both potential monetary gains and losses. We further report that ex-smokers showed a significantly greater activation change in the ventral putamen compared with both controls and smokers and in the caudate compared with controls during the anticipation of potential monetary losses only. The results suggest that smoking may sensitize striato-orbitofrontal circuitry subserving motivational processes for loss avoidance and reward gain in nicotine addiction.Ex-smokers and smokers show significantly greater activation changes (*p 
      PubDate: 2016-12-12T01:50:54.866197-05:
      DOI: 10.1111/adb.12484
  • Distinct intrinsic functional brain network abnormalities in
           methamphetamine-dependent patients with and without a history of psychosis
    • Authors: Jonathan C. Ipser; Anne Uhlmann, Paul Taylor, Brian H. Harvey, Don Wilson, Dan J. Stein
      Abstract: Chronic methamphetamine use is associated with executive functioning deficits that suggest dysfunctional cognitive control networks (CCNs) in the brain. Likewise, abnormal connectivity between intrinsic CCNs and default mode networks (DMNs) has also been associated with poor cognitive function in clinical populations. Accordingly, we tested the extent to which methamphetamine use predicts abnormal connectivity between these networks, and whether, as predicted, these abnormalities are compounded in patients with a history of methamphetamine-associated psychosis (MAP). Resting-state fMRI data were acquired from 46 methamphetamine-dependent patients [19 with MAP, 27 without (MD)], as well as 26 healthy controls (CTRL). Multivariate network modelling and whole-brain voxel-wise connectivity analyses were conducted to identify group differences in intrinsic connectivity across four cognitive control and three DMN networks identified using an independent components analysis approach (meta-ICA). The relationship of network connectivity and psychotic symptom severity, as well as antipsychotic treatment and methamphetamine use variables, was also investigated. Robust evidence of hyper-connectivity was observed between the right frontoparietal and anterior DMN networks in MAP patients, and ‘normalized’ with increased duration of treatment with antipsychotics. Attenuation of anticorrelated anterior DMN–dorsal attention network activity was also restricted to this group. Elevated coupling detected in MD participants between anterior and posterior DMN networks became less apparent with increasing duration of abstinence from methamphetamine. In summary, we observed both alterations of RSN connectivity between DMN networks with chronic methamphetamine exposure, as well as DMN-CCN coupling abnormalities consistent with possible MAP-specific frontoparietal deficits in the biasing of task-appropriate network activity.Abnormal connectivity was observed between intrinsic functional cognitive control networks and task-negative default mode networks in the brains of 19 patients with a history of methamphetamine-associated psychosis. Connectivity approached levels observed in 26 healthy controls with increasing antipsychotic treatment duration. Hyperconnectivity between default mode networks was restricted to 27 methamphetamine-dependent patients without methamphetamine-associated psychosis, “normalizing” with longer abstinence.
      PubDate: 2016-12-05T01:58:14.416491-05:
      DOI: 10.1111/adb.12478
  • Putamen functional connectivity during inhibitory control in smokers and
    • Authors: Sophie E. A. Akkermans; Maartje Luijten, Daan Rooij, Ingmar H. A. Franken, Jan K. Buitelaar
      Abstract: The putamen has been shown to play a key role in inhibitory control and addiction, and consists of distinct subregions associated with distinct functions. The anterior putamen is thought to be specialized in goal-directed control or response-monitoring in connection with frontal regions, whereas the posterior part is specialized in habitual or automatic responding in connection with sensorimotor regions. The present study is the first to delineate functional networks of the anterior and posterior putamen in a Go–NoGo response inhibition task, and to examine differences between smokers (n = 25) and non-smokers (n = 23) within these networks. Functional connectivity analyses were conducted on fMRI data from a Go–NoGo study, using the generalized form of psychophysiological interaction with anterior and posterior putamen seed regions. In the context of inhibition, the anterior putamen exhibited connectivity with the anterior cingulate cortex (ACC) and precuneus (pFWE 
      PubDate: 2016-12-05T01:58:08.03948-05:0
      DOI: 10.1111/adb.12482
  • Comparing rewarding and reinforcing properties between ‘bath salt’
           3,4-methylenedioxypyrovalerone (MDPV) and cocaine using ultrasonic
           vocalizations in rats
    • Authors: Steven J. Simmons; Ryan A. Gregg, Fionya H. Tran, Lili Mo, Eva Weltin, David J. Barker, Taylor A. Gentile, Lucas R. Watterson, Scott M. Rawls, John W. Muschamp
      Abstract: Abuse of synthetic psychostimulants like synthetic cathinones has risen in recent years. 3,4-Methylenedioxypyrovalerone (MDPV) is one such synthetic cathinone that demonstrates a mechanism of action similar to cocaine. Compared to cocaine, MDPV is more potent at blocking dopamine and norepinephrine reuptake and is readily self-administered by rodents. The present study compared the rewarding and reinforcing properties of MDPV and cocaine using systemic injection dose-response and self-administration models. Fifty kilohertz ultrasonic vocalizations (USVs) were recorded as an index of positive affect throughout experiments. In Experiment 1, MDPV and cocaine dose-dependently elicited 50-kHz USVs upon systemic injection, but MDPV increased USVs at greater rates and with greater persistence relative to cocaine. In Experiment 2, latency to begin MDPV self-administration was shorter than latency to begin cocaine self-administration, and self-administered MDPV elicited greater and more persistent rates of 50-kHz USVs versus cocaine. MDPV-elicited 50-kHz USVs were sustained over the course of drug load-up whereas cocaine-elicited USVs waned following initial infusions. Notably, we observed a robust presence of context-elicited 50-kHz USVs from both MDPV and cocaine self-administering rats. Collectively, these data suggest that MDPV has powerfully rewarding and reinforcing effects relative to cocaine at one-tenth doses. Consistent with prior work, we additionally interpret these data in supporting that MDPV has significant abuse risk based on its potency and subjectively positive effects. Future studies will be needed to better refine therapeutic strategies targeted at reducing the rewarding effects of cathinone analogs in efforts to ultimately reduce abuse liability.Our work shows that the synthetic cathinone 3,4-methylenedioxypyrovalerone evokes sustained rewarding effects (assessed via 50-kHz ultrasonic vocalizations) in systemic dose-response and self-administration models compared with cocaine. Results extend growing literature on abuse liability associated with novel psychoactive substances including cathinone analogs. Future work should identify neuronal circuits governing positive subjective effects of 3,4-methylenedioxypyrovalerone that in turn direct drug-seeking behavior.
      PubDate: 2016-12-01T23:57:18.219847-05:
      DOI: 10.1111/adb.12479
  • Craving behavioral intervention for internet gaming disorder: remediation
           of functional connectivity of the ventral striatum
    • Authors: Jin-Tao Zhang; Shan-Shan Ma, Chiang-Shan R. Li, Lu Liu, Cui-Cui Xia, Jing Lan, Ling-Jiao Wang, Ben Liu, Yuan-Wei Yao, Xiao-Yi Fang
      Abstract: Psychobehavioral intervention is an effective treatment of Internet addiction, including Internet gaming disorder (IGD). However, the neural mechanisms underlying its efficacy remain unclear. Cortical-ventral striatum (VS) circuitry is a common target of psychobehavioral interventions in drug addiction, and cortical-VS dysfunction has been reported in IGD; hence, the primary aim of the study was to investigate how the VS circuitry responds to psychobehavioral interventions in IGD. In a cross-sectional study, we examined resting-state functional connectivity of the VS in 74 IGD subjects (IGDs) and 41 healthy controls (HCs). In a follow-up craving behavioral intervention (CBI) study, of the 74 IGD subjects, 20 IGD subjects received CBI (CBI+) and 16 IGD subjects did not (CBI−). All participants were scanned twice with similar time interval to assess the effects of CBI. IGD subjects showed greater resting-state functional connectivity of the VS to left inferior parietal lobule (lIPL), right inferior frontal gyrus and left middle frontal gyrus, in positive association with the severity of IGD. Moreover, compared with CBI−, CBI+ showed significantly greater decrease in VS-lIPL connectivity, along with amelioration in addiction severity following the intervention. These findings demonstrated that functional connectivity between VS and lIPL, each presumably mediating gaming craving and attentional bias, may be a potential biomarker of the efficacy of psychobehavioral intervention. These results also suggested that non-invasive techniques such as transcranial magnetic or direct current stimulation targeting the VS-IPL circuitry may be used in the treatment of Internet gaming disorders.Internet gaming disorder subjects showed greater resting-state functional connectivity of ventral striatum to left inferior parietal lobule, right inferior frontal gyrus, and left middle frontal gyrus. The strength of ventral striatum-left inferior parietal lobule connectivity was reduced, along with amelioration in addiction severity following the craving behavioral intervention.
      PubDate: 2016-11-28T17:55:38.214331-05:
      DOI: 10.1111/adb.12474
  • Cue-induced nicotine-seeking behavior after withdrawal with or without
           extinction in rats
    • Authors: Athina Markou; Jie Li, Kearny Tse, Xia Li
      Abstract: Exposure to smoking-associated environmental cues during smoke cessation elicits self-reported urge/craving to smoke, which precipitates relapse even after prolonged abstinence. Incubation of cue-induced cigarettes craving during abstinence has been observed in human smokers recently. The present studies assessed cue-induced nicotine-seeking behavior under different withdrawal conditions in rats with a history of nicotine self-administration. We found that non-reinforced operant responding during cue-induced nicotine seeking after different periods of withdrawal from nicotine exhibited an inverted U-shaped curve, with higher levels of responding after 7–21 days of withdrawal than those after 1-day withdrawal. Cue-induced nicotine-seeking responding is long lasting and persists even after 42 days of forced withdrawal in the home cages. Interestingly, repeated testing of cue-induced nicotine seeking at different withdrawal time points (1, 7, 14, 21 and 42 days) in the same individual alleviated responding as compared with the between-subjects assessment. Furthermore, extinction training during nicotine withdrawal significantly decreased cue-induced reinstatement of nicotine-seeking behavior. Together, profound time-dependent incubation of cue-induced craving in nicotine-experienced rats were observed. In addition, repeated cue exposure or extinction training decreases cue-induced craving. The demonstration of incubation of nicotine craving phenomenon in both rat and human studies provides support for the translational potential of therapeutic targets for relapse uncovered through mechanism studies in rats.The present studies show the profound time-dependent changes in cue-induced nicotine-seeking behavior under different withdrawal conditions in nicotine-experienced rats. Non-reinforced operant responding during cue-induced nicotine seeking after different periods of withdrawal from nicotine exhibited an inverted U-shaped curve, with higher levels of responding after 7–21 days of withdrawal than those after 1-day or 42-day withdrawal.
      PubDate: 2016-11-28T17:55:26.559502-05:
      DOI: 10.1111/adb.12480
  • Impact of alcohol use on EEG dynamics of response inhibition: a cotwin
           control analysis
    • Authors: Jeremy Harper; Stephen M. Malone, William G. Iacono
      Abstract: Research indicates that alcohol misuse is associated with behavioral disinhibition, but the neurophysiological mechanisms governing this relationship remain largely unknown. Recent work suggests that successful inhibition and cognitive control involve electrophysiological theta-band dynamics, including medial frontal cortex (MFC) power enhancement and functional connectivity between the MFC and dorsal prefrontal cortex (dPFC) regions, which may be disrupted by alcohol misuse. In addition, research suggests that, compared to men, women are at heightened risk of experiencing the negative physical and neurocognitive correlates of drinking. The present study tested the hypothesis that alcohol misuse has a deleterious effect on theta-band response inhibition EEG dynamics in a sample of 300 24-year-old same-sex twins. A cotwin control (CTC) design was used to disentangle premorbid risk for alcohol use from the causal effects of alcohol exposure. Drinking was negatively associated with theta-band MFC power and MFC–dPFC connectivity during response inhibition, and this effect was stronger among women. The CTC analysis suggested that, for women, reduced nogo-related theta-band MFC power and MFC–dPFC connectivity were both consistent with the potential deleterious causal effects of alcohol exposure. These findings suggest that diminished theta-band MFC power and MFC–dPFC connectivity may be neurophysiological mechanisms underlying alcohol-related disinhibition. Although preliminary, these results suggest that normative levels of alcohol use during emerging adulthood have potential sex-specific causal effects on response inhibition EEG dynamics, and thus have potentially significant public health implications.In a large (N = 300) population-based sample of 24-year-old twins, alcohol use was negatively associated with EEG theta-band medial frontal cortex power and medial-dorsal prefrontal cortex functional connectivity during response inhibition, and this effect was stronger among women. A cotwin analysis suggested that, for women, reduced nogo-related theta-band dynamics were consistent with the potential deleterious causal effects of alcohol exposure.
      PubDate: 2016-11-18T03:00:35.826198-05:
      DOI: 10.1111/adb.12481
  • Low-level alcohol consumption during adolescence and its impact on
           cognitive control development
    • Authors: Sarah Jurk; Eva Mennigen, Thomas Goschke, Michael N. Smolka
      Abstract: Adolescence is a critical period for maturation of cognitive control and most adolescents start experimenting with alcohol around that time. On the one hand, recent studies indicate that low control abilities predict future problematic alcohol use. On the other hand, binge drinking during young adulthood can (further) impair cognitive control. However, so far no study examined the effects of low-level alcohol use during adolescence. In the present longitudinal fMRI study, we therefore investigated the development of cognitive control in a community-based sample of 92 adolescents at ages 14, 16 and 18. Two different cognitive control functions, i.e. inhibition of pre-potent responses (operationalized by incongruence effects) and switching between different task sets, were measured within one task. Alcohol use in our sample was low (mean: 54 g/week at age 18). The study revealed that neither behavioural nor neural measures of cognitive control function at age 14 predicted alcohol use at age 18 but confirmed established predictors such as gender and personality. As expected, from age 14 to 18, cognitive control abilities were improving (decreased reaction times and/or errors), and activation of cognitive control networks (dorsal anterior cingulate cortex and pre-supplementary motor area) during incongruent trials increased. Unexpectedly, higher alcohol consumption during adolescence was associated with a more pronounced increase in cognitive performance and a smaller increase of neural activation when incongruent trials afforded inhibitory control. We conclude that low-level alcohol use during adolescence does not severely impair ongoing maturation of cognitive control abilities and networks.Investigating the relationship between the development of cognitive control and alcohol consumption across adolescence, we found that neither behavioural nor neural measures of cognitive control at age 14 predicted alcohol use at age 18. As expected, cognitive control abilities and activation of involved brain networks increased from age 14 to 18. Nevertheless, low-level alcohol consumption did not impair ongoing maturation.
      PubDate: 2016-11-17T00:35:59.166817-05:
      DOI: 10.1111/adb.12467
  • Methamphetamine self-administration reduces alcohol consumption and
           preference in alcohol-preferring P rats
    • Authors: Madeline C. Winkler; Emilee M. Greager, Jacob Stafford, Ryan K. Bachtell
      Abstract: Subclinical levels of polysubstance use are a prevalent and understudied phenomenon. Alcohol is a substance commonly co-used with other substances of other drug classes. These studies sought to determine the consumption effects of combining alcohol drinking and methamphetamine (MA) self-administration. Male alcohol-preferring P rats had continuous access to a two-bottle alcohol drinking procedure in the home cage. Control rats remained alcohol naïve. Rats were also surgically implanted with intra-jugular catheters and trained to self-administer saline (control) or MA in daily 2-hour sessions. We first measured the acquisition and maintenance of MA intake in alcohol-consuming or control rats. MA intake was initially enhanced by alcohol consumption on a fixed ratio 1 schedule of reinforcement, but this effect did not prevail as the difficulty of the schedule (FR5 and progressive ratio) was increased. We next measured both alcohol consumption and preference before, during and after MA (or saline) self-administration. MA self-administration significantly reduced alcohol intake and preference ratios, a robust effect that persisted across several experimental variations. Interestingly, alcohol consumption rebounded following the cessation of MA self-administration. The effects of MA self-administration were specific to alcohol intake because it did not alter total fluid consumption or consumption of sucrose. MA self-administration did not impact blood-alcohol concentrations or alcohol-induced loss of righting reflex suggesting no effect of MA intake on the alcohol metabolism or sensitivity. Together, the results suggest that MA intake disrupts alcohol consumption and preferences but not the reverse in alcohol-preferring P rats.Self-administration of methamphetamine in alcohol-preferring P rats disrupts alcohol consumption and preference. These effects are restricted to the period of co-use and do not produce persistent effects beyond the co-use period. Although not depicted in this figure, alcohol consumption does not produce reliable, robust effects on methamphetamine intake.
      PubDate: 2016-11-16T02:13:29.7062-05:00
      DOI: 10.1111/adb.12476
  • Characterization of hangover following intravenous alcohol exposure in
           social drinkers: methodological and clinical implications
    • Authors: Vatsalya Vatsalya; Bethany L. Stangl, Veronica Y. Schmidt, Vijay A. Ramchandani
      Abstract: Hangover refers to the cluster of physiological and behavioral symptoms that occur following the end of a drinking episode. While hangover has been studied after the typical oral consumption of alcohol, the occurrence of hangover following intravenous (IV) alcohol administration in human laboratory studies has not been previously reported. This study characterizes hangover symptoms and post-infusion drinking behavior following acute IV alcohol administration in social drinkers. Twenty-one to thirty-year-old healthy social drinkers (n = 24) underwent an alcohol clamp session at breath alcohol concentration of 0.06 percent. Hangover symptoms as well as any post-infusion drinking that occurred between the end of the session and the following morning were assessed using the Acute Hangover Scale, and examined for influences of recent drinking history, family history of alcoholism and Sex. Results indicated a 79 percent prevalence of hangover symptoms, with the most common symptoms being ‘tired’, ‘thirsty’ and ‘headache’. Recent drinking measures showed significant effects on Average Hangover Scale scores, with heavier drinkers showing greater hangover symptoms. There was a significant sex difference in average hangover scores, with females reporting higher scores than males. Subjective measures of stimulation and intoxication were also associated with Average Hangover Scale scores. The probability of post-infusion drinking was not predicted by hangover scores, but was related to recent drinking history; subjective response to alcohol was a significant mediator of this relationship. These findings demonstrate that hangover symptoms are experienced following IV alcohol administration, and extend previous studies of influences of risk factors for alcohol use disorders including recent drinking on hangover.“This study characterized hangover symptoms after IV alcohol in social drinkers. There was a 79% prevalence of hangover following a 0.06 g% alcohol clamp. Females and heavier drinkers reported greater hangover symptoms. Self-reported stimulation and intoxication were also associated with hangover. These findings extend previous research on association of hangover with risk factors for alcohol use disorders including drinking history.”
      PubDate: 2016-11-11T02:06:22.425556-05:
      DOI: 10.1111/adb.12469
  • PPARγ agonism attenuates cocaine cue reactivity
    • Authors: William R Miller; Robert G Fox, Sonja J Stutz, Scott D Lane, Larry Denner, Kathryn A Cunningham, Kelly T Dineley
      Abstract: Cocaine use disorder is a chronic relapsing condition characterized by compulsive drug seeking and taking even after prolonged abstinence periods. Subsequent exposure to drug-associated cues can promote intense craving and lead to relapse in abstinent humans and rodent models. The responsiveness to these cocaine-related cues, or ‘cue reactivity’, can trigger relapse and cocaine-seeking behaviors; cue reactivity is measurable in cocaine-dependent humans as well as rodent models. Cue reactivity is thought to be predictive of cocaine craving and relapse. Here we report that PPARγ agonism during abstinence from cocaine self-administration reduced previously active lever pressing in Sprague Dawley rats during cue-reactivity tests, while administration of the PPARγ antagonist, GW9662, reversed this effect. PPARγ agonism also normalized nuclear ERK activity in the medial prefrontal cortex and hippocampus which was reversed with GW9662. Our results support the utility of PPARγ agonism as a relapse prevention strategy to maintain abstinence in the presence of cocaine-associated cues.Our previous work discovered that extracellular signal-regulated kinase (ERK) interacts with the nuclear receptor and transcription factor, peroxisome proliferator activated receptor gamma (PPARγ), in a dynamic multiprotein complex that facilitates ERK/CREB/CBP-dependent memory consolidation. Abstinence from cocaine self-administration leads to ERK dysregulation and enhanced cue reactivity. We found that PPARγ agonism attenuates cocaine cue reactivity and normalizes ERK. Thus, PPARγ agonism may counteract cocaine cue reactivity and extend abstinence.
      PubDate: 2016-11-11T02:00:26.325712-05:
      DOI: 10.1111/adb.12471
  • The role of CA3-LS-VTA loop in the formation of conditioned place
           preference induced by context-associated reward memory for morphine
    • Authors: Jin-Xiang Jiang; Huan Liu, Zhen-Zhen Huang, Yue Cui, Xue-Qin Zhang, Xiao-Long Zhang, Yu Cui, Wen-Jun Xin
      Abstract: Addiction-related behaviors, such as conditioned place preference (CPP), require animals to remember an association between environmental cue and drug treatment, and exposure to environmental cue is one of the key contributing factors to relapse. However, how central neural circuit participates in the formation of CPP induced by stimulus of morphine-paired environment remains unknown. In the present study, we found that reexposure to morphine-paired environment significantly increased the activity of hippocampal CA3 neurons, increased the excitability of GABAergic neurons and expression of glutamic acid decarboxylase 65/67 in the caudal lateral septum (LSc) and decreased the activity of GABAergic neurons and GAD65/67 expression in ventral tegmental area (VTA), leading to activation (disinhibition) of dopaminergic neurons. Inactivation of CA3 neurons attenuated GABAergic neurons activity and decreased the upregulation of GAD65/67 in LSc, prevented the dopaminergic neurons activation,and GAD65/67 downregulation in VTA and ameliorated the CPP behavior following exposure to morphine-paired context. Blockade of NMDA receptor in LSc also prevented the upregulation of GAD65/67 in LSc and formation of CPP induced by stimulus of morphine-paired environment. Suppression of GAD activity in LSc also remarkably attenuated the dopaminergic neurons activation and the GAD65/67 downregulation in VTA and prevented the formation of CPP induced by reexposure to morphine-associated context. Collectively, these results, for the first time, illustrated the involvement of neural circuitry of CA3-LSc-VTA, through integration of the contexts and reward information, participated in the reinstatement of CPP induced by exposure to morphine-associated context, which advanced our understanding on neurobiological basis for the context-associated memory and rewarding behavior.These results, for the first time, illustrated the involvement of neural circuitry of CA3-LSc-VTA, through integration of the contexts and reward information, participated in the reinstatement of conditioned place preference induced by exposure to morphine-associated context, which advanced our understanding on neurobiological basis for the context-associated memory and rewarding behavior.
      PubDate: 2016-11-11T01:50:30.31912-05:0
      DOI: 10.1111/adb.12468
  • Repeated restraint stress exposure during early withdrawal accelerates
           incubation of cue-induced cocaine craving
    • Authors: Ryan M. Glynn; J. Amiel Rosenkranz, Marina E. Wolf, Aaron Caccamise, Freya Shroff, Alyssa B. Smith, Jessica A. Loweth
      Abstract: A major challenge for treating cocaine addiction is the propensity for abstinent users to relapse. Two important triggers for relapse are cues associated with prior drug use and stressful life events. To study their interaction in promoting relapse during abstinence, we used the incubation model of craving and relapse in which cue-induced drug seeking progressively intensifies (‘incubates’) during withdrawal from extended-access cocaine self-administration. We tested rats for cue-induced cocaine seeking on withdrawal day (WD) 1. Rats were then subjected to repeated restraint stress or control conditions (seven sessions held between WD6 and WD14). All rats were tested again for cue-induced cocaine seeking on WD15, 1 day after the last stress or control session. Although controls showed a time-dependent increase in cue-induced cocaine seeking (incubation), rats exposed to repeated stress in early withdrawal exhibited a more robust increase in seeking behavior between WD1 and WD15. In separate stressed and control rats, equivalent cocaine seeking was observed on WD48. These results indicate that repeated stress in early withdrawal accelerates incubation of cocaine craving, although craving plateaus at the same level were observed in controls. However, 1 month after the WD48 test, rats subjected to repeated stress in early withdrawal showed enhanced cue-induced cocaine seeking following acute (24 hours) food deprivation stress. Together, these data indicate that chronic stress exposure enhances the initial rate of incubation of craving during early withdrawal, resulting in increased vulnerability to cue-induced relapse during this period, and may lead to a persistent increase in vulnerability to the relapse-promoting effects of stress.During the first month of withdrawal from extended-access cocaine self-administration, cue-induced cocaine seeking progressively intensifies (‘incubates’). We found that repeated restraint stress exposure during the first 2 weeks of withdrawal accelerates this incubation process in adult male rats and may make these animals more susceptible to the relapse-promoting effects of a subsequent stressful episode.
      PubDate: 2016-11-11T01:40:32.279692-05:
      DOI: 10.1111/adb.12475
  • Metabolic alterations in the anterior cingulate cortex and related
           cognitive deficits in late adolescent methamphetamine users
    • Authors: Jieun E. Kim; Geon Ha Kim, Jaeuk Hwang, Jung Yoon Kim, Perry F. Renshaw, Deborah A. Yurgelun-Todd, Binna Kim, Ilhyang Kang, Saerom Jeon, Jiyoung Ma, In Kyoon Lyoo, Sujung Yoon
      Abstract: The adolescent brain, with ongoing prefrontal maturation, may be more vulnerable to drug use-related neurotoxic changes as compared to the adult brain. We investigated whether the use of methamphetamine (MA), a highly addictive psychostimulant, during adolescence affect metabolic and cognitive functions of the anterior cingulate cortex (ACC). In adolescent MA users (n = 44) and healthy adolescents (n = 53), the levels of N-acetyl aspartate (NAA), a neuronal marker, were examined in the ACC using proton magnetic resonance spectroscopy. The Stroop color–word task was used to assess Stroop interference, which may reflect cognitive functions of behavior monitoring and response selection that are mediated by the ACC. Adolescent MA users had lower NAA levels in the ACC (t = −2.88, P = 0.005) and relatively higher interference scores (t = 2.03, P = 0.045) than healthy adolescents. Moreover, there were significant relationships between lower NAA levels in the ACC and worse interference scores in adolescent MA users (r = −0.61, P 
      PubDate: 2016-11-04T00:16:56.493995-05:
      DOI: 10.1111/adb.12473
  • Effects of high-dose ethanol intoxication and hangover on cognitive
    • Authors: Nicole Wolff; Philipp Gussek, Ann-Kathrin Stock, Christian Beste
      Abstract: The effects of high-dose ethanol intoxication on cognitive flexibility processes are not well understood, and processes related to hangover after intoxication have remained even more elusive. Similarly, it is unknown in how far the complexity of cognitive flexibility processes is affected by intoxication and hangover effects. We performed a neurophysiological study applying high density electroencephalography (EEG) recording to analyze event-related potentials (ERPs) and perform source localization in a task switching paradigm which varied the complexity of task switching by means of memory demands. The results show that high-dose ethanol intoxication only affects task switching (i.e. cognitive flexibility processes) when memory processes are required to control task switching mechanisms, suggesting that even high doses of ethanol compromise cognitive processes when they are highly demanding. The EEG and source localization data show that these effects unfold by modulating response selection processes in the anterior cingulate cortex. Perceptual and attentional selection processes as well as working memory processes were only unspecifically modulated. In all subprocesses examined, there were no differences between the sober and hangover states, thus suggesting a fast recovery of cognitive flexibility after high-dose ethanol intoxication. We assume that the gamma-aminobutyric acid (GABAergic) system accounts for the observed effects, while they can hardly be explained by the dopaminergic system.High dose ethanol intoxication affects switching in conditions that involve working memory processes, while switching without memory load remains unaffected. These modulations are accompanied by corresponding effects in the anterior cingulate cortex. During states of sober and hangover, no differences were observed, suggesting that the results seem unlikely to be explained via the dopaminergic system but via the gamma aminobutyric acid system.
      PubDate: 2016-10-27T20:30:59.734349-05:
      DOI: 10.1111/adb.12470
  • The new designer drug buphedrone produces rewarding properties via
           dopamine D1 receptor activation
    • Authors: Ji-Hwan Oh; Ji-Young Hwang, Sa-Ik Hong, Shi-Xun Ma, Jee-Yeon Seo, Seok-Yong Lee, Hyoung-Chun Kim, Choon-Gon Jang
      Abstract: Substituted cathinones are synthetic analogs of the active components of natural products and are widely abused worldwide. However, the rewarding properties of these agents have not yet been evaluated. In this study, we investigated the abuse potential of buphedrone [2-(methylamino)-1-phenylbutan-1-one, α-methylamino-butyrophenone] and its effects on the mesolimbic dopaminergic system in mice using conditioned place preference (CPP) analysis, a self-administration test, a locomotor activity test, a behavioral sensitization test and Western blot analysis. Treatment with buphedrone supported CPP and self-administration, enhanced locomotor activity and produced behavioral sensitization when mice were challenged with methamphetamine. SCH23390, a D1 dopamine antagonist, prevented buphedrone-induced CPP, whereas raclopride, a D2 dopamine antagonist, had no effect. SCH23390 also blocked locomotor activity increase by buphedrone, while raclopride partially attenuated locomotor activation. Western blot analysis revealed that repeated buphedrone treatment increased D1 dopamine receptor expression in the dorsal striatum and nucleus accumbens in mice. Collectively, these findings suggest the abuse potential of buphedrone and demonstrate the involvement of the dopaminergic system in the establishment of its rewarding properties.Substituted cathinones are widely abused worldwide. In this study, buphedrone, a type of cathinone, increased conditioned place preference, self-administration, locomotor activity, and induced behavioral sensitization. The rewarding property of buphedrone may be through dopamine D1 receptor activation.
      PubDate: 2016-10-27T20:30:55.892078-05:
      DOI: 10.1111/adb.12472
  • A clinical trial with combined transcranial direct current stimulation and
           alcohol approach bias retraining
    • Authors: Tess E. Uyl; Thomas E. Gladwin, Mike Rinck, Johannes Lindenmeyer, Reinout W. Wiers
      Abstract: Two studies showed an improvement in clinical outcomes after alcohol approach bias retraining, a form of Cognitive Bias Modification (CBM). We investigated whether transcranial direct current stimulation (tDCS) could enhance effects of CBM. TDCS is a neuromodulation technique that can increase neuroplasticity and has previously been found to reduce craving. One hundred alcohol-dependent inpatients (91 used for analysis) were randomized into three experimental groups in a double-blind parallel design. The experimental group received four sessions of CBM while receiving 2 mA of anodal tDCS over the dorsolateral prefrontal cortex (DLPFC). There were two control groups: One received sham stimulation during training and one received active stimulation at a different moment. Treatment outcomes were abstinence duration (primary) and relapse after 3 and 12 months, craving and approach bias (secondary). Craving and approach bias scores decreased over time; there were no significant interactions with experimental condition. There was no effect on abstinence duration after three months (χ2(2) = 3.53, p = 0.77). However, a logistic regression on relapse rates after one year (standard outcome in the clinic, but not-preregistered) showed a trend when relevant predictors were included; relapse was lower in the condition receiving active stimulation during CBM only when comparing to sham stimulation (B = 1.52, S.E. = .836, p = .07, without predictors: p = .19). No strong evidence for a specific enhancement effect of tDCS on CBM was found. However, in a post-hoc analysis, tDCS combined with CBM showed a promising trend on treatment outcome. Important limitations are discussed, and replication is necessary to find more reliable effects.This study investigated whether 2 mA of transcranial direct current stimulation (tDCS) on the dorsolateral prefrontal cortex could enhance effects of four sessions of cognitive bias modification (CBM). No strong evidence for a specific enhancement effect of tDCS on CBM was found. In a post-hoc analysis, tDCS combined with CBM did show a promising trend on treatment outcome.
      PubDate: 2016-10-27T20:30:50.129222-05:
      DOI: 10.1111/adb.12463
  • Increase of KCC2 in hippocampal synaptic plasticity disturbances after
           perinatal ethanol exposure
    • Authors: Benoît Silvestre de Ferron; Catherine Vilpoux, Myriam Kervern, Alexandre Robert, Johan Antol, Mickael Naassila, Olivier Pierrefiche
      Abstract: Low to moderate perinatal ethanol exposure (PEE) may have disastrous consequences for the central nervous system resulting notably in permanent cognitive deficits. Learning and memory are mediated in the hippocampus by long-term potentiation (LTP) and long term depression (LTD), two forms of synaptic plasticity. PEE decreases LTP but also abnormally facilitates LTD (Kervern et al. ) through a presently unknown mechanism. We studied in rat hippocampus slice, the involvement of the chloride co-transporters NKCC1 and KCC2, in the role of GABAA inhibitions in facilitated LTD after moderate PEE. After PEE and in contrast to control slices, facilitated LTD in CA1 field was reduced by the GABAA receptor antagonist bicuculline with no changes in sensitivity to bicuculline and in GABA and benzodiazepine binding sites. Also, sensitivity to diazepam was unaltered, whereas aberrant LTD was blocked. Immunohistochemistry and protein analysis demonstrated an increase in KCC2 protein level at cell membrane in CA1 after PEE with no change in NKCC1 expression. Specifically, both monomeric and dimeric forms of KCC2 were increased in CA1. Bumetanide (10–100 μM), a dose-dependent blocker of NKCC1 and KCC2, or VU0240551 (10 μM) a specific antagonist of KCC2, corrected the enhanced LTD and interestingly bumetanide also restored the lower LTP after PEE. These results demonstrate for the first time an upregulation of the KCC2 co-transporter expression after moderate PEE associated with disturbances in GABAergic neurotransmission modulating bidirectional synaptic plasticity in the hippocampus. Importantly, bumetanide compensated deficits in both LTP and LTD, revealing its potential therapeutic properties.In rat CA1 pyramidal cell, ethanol exposure during brain development disturbs long-term synaptic plasticity via an increase in the role of KCC2 co-transporter. Bumetanide, a dose-dependent blocker of the two chloride cotransporters NKCC1 and KCC2 help restoring new equilibrium between the roles of these transporters.
      PubDate: 2016-10-25T01:45:41.123706-05:
      DOI: 10.1111/adb.12465
  • Region specific activation of the AKT and mTORC1 pathway in response to
           excessive alcohol intake in rodents
    • Authors: Sophie Laguesse; Nadege Morisot, Khanhky Phamluong, Dorit Ron
      Abstract: We previously reported that the kinase AKT is activated in the nucleus accumbens (NAc) of rodents in response to excessive consumption of alcohol. One of the important downstream targets of AKT is the mammalian Target Of Rapamycin in Complex 1 (mTORC1), which was also activated by alcohol intake. mTORC1 controls dendritic protein translation, and we showed that the mTORC1-dependent translational machinery is activated in the NAc in response to alcohol intake. Importantly, systemic or intra-NAc inhibition of the AKT/mTORC1 pathway attenuated alcohol-drinking behaviors. Here, we mapped the activation patterns of AKT and mTORC1 in corticostriatal regions of rodents consuming large amounts of alcohol. We found that the activation of AKT and mTORC1 in response to cycles of binge drinking of 20 percent alcohol was centered in the NAc shell. Both kinases were not activated in the dorsolateral striatum (DLS); however, AKT, but not mTORC1, was activated in the dorsomedial striatum (DMS) of mice but not rats. Interestingly, excessive intake of alcohol produced a selective activation of the AKT/mTORC1 pathway in the orbitofrontal cortex (OFC), which was not observed in medial prefrontal cortex (mPFC). Furthermore, this signaling pathway was not activated in the NAc shell or OFC of rats consuming moderate amounts of alcohol nor was it activated in rats consuming sucrose. Together, our results suggest that excessive alcohol intake produces a brain region selective activation of the AKT/mTORC1 pathway, which is likely to contribute to NAc shell and OFC-dependent mechanisms that underlie the development and maintenance of alcohol drinking behavior.Excessive alcohol intake, but not moderate alcohol or sucrose consumption, produces a brain region selective activation of the AKT/mTORC1 pathway in the nucleus accumbens shell and the orbitofrontal cortex of rodents, which is likely to contribute to local molecular mechanisms that underlie the development and maintenance of alcohol drinking behavior.
      PubDate: 2016-10-20T19:20:37.51588-05:0
      DOI: 10.1111/adb.12464
  • Evidence for GABA-A receptor dysregulation in gambling disorder:
           correlation with impulsivity
    • Authors: Inge Mick; Anna C. Ramos, Jim Myers, Paul R. Stokes, Samantha Chandrasekera, David Erritzoe, Maria A. Mendez, Roger N. Gunn, Eugenii A. Rabiner, Graham E. Searle, José C. F. Galduróz, Adam D. Waldman, Henrietta Bowden-Jones, Luke Clark, David J. Nutt, Anne R. Lingford-Hughes
      Abstract: As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11C]Ro15-4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [11C]Ro15-4513 total distribution volume (VT) in the right hippocampus in the GD group compared with HV. We found higher levels of the ‘Negative Urgency’ construct of impulsivity in GD, and these were positively associated with higher [11C]Ro15-4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioural addictions. These results provide the first characterization of GABAA receptors in GD with [11C]Ro15-4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment.We used [11C]Ro15–4513 PET to assess GABA-a5 receptor availability in gambling disorder (GD) and impulsivity. We found significantly higher [11C]Ro15–4513 total distribution volume (VT) in the right hippocampus in GD compared with healthy volunteers. We found higher levels of The ‘Negative Urgency’ construct of impulsivity in GD that positively associated with higher [11C]Ro15–4513 VT in the amygdala in the GD group; no such significant correlations were evident in the healthy volunteers group.
      PubDate: 2016-10-13T20:35:49.927892-05:
      DOI: 10.1111/adb.12457
  • Progressive white matter impairment as a predictor of outcome in a cohort
           of opioid-dependent patient's post-detoxification
    • Authors: Jo-Hanna Ivers; Jacqueline Fitzgerald, Christopher Whelan, Brion Sweeney, Eamon Keenan, Andrew Fagan, Jason McMarrow, Jim Meany, Joe Barry, Thomas Frodl
      Abstract: White matter impairment is associated with opioid dependence. However, the specific neuropathology related to opioid dependence is still not fully understood. The main aims of this study were to: (1) assess the association between white matter impairment and duration of dependence; (2) examine whether this impairment correlates with treatment outcome measures in opioid-dependent patients post-detoxification. Fifty-eight opioid-dependent patients participated, 20 females and 38 males, across three groups: less than 10 years use (n = 18), 10–15 years use (n = 26) and 16–25+ years use (n = 14). Diffusion tensor imaging was used to assess white matter impairment; whole brain voxel-wise analysis of fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were performed by Tract-Based-Spatial-Statistics to pinpoint abnormalities in white matter. The longer the subjects were dependent on opioids, the more widespread and severely the white-matter integrity was disrupted. A general linear model was used to examine patients who relapsed compared to those who were abstinent at follow-up. No statistical difference was found between groups (p > 0.05). Partial correlations were performed to investigate the relationship between clinical outcome measures (physical health, psychological well being and quality of life and hope for the future) and white-matter microstructural differences. Significant correlations were found between AD in the posterior corona radiata (L) and MD in the superior longitudinal fasciculus and a clinical measure for HOPE at 9-month follow-up. Nevertheless, it must be noted that the calculation of numerous correlations raises the possibility of a type I error, namely; to incorrectly conclude the occurrence of a significant correlation. The ability to investigate the structure–clinical relationship may improve our understanding of the pathological abnormalities associated with opioid dependence and has promise for use in evaluating future therapeutic outcomes in this population.The scale and extent of white matter impairment in opioid-dependent patients may be associated with duration of use.The change between connections in subcortical regions is pronounced in long-term users compared with short-term and medium-term users.The consequence of changes in the subcortical region has serious repercussions for opioid-dependent patients, as the struggle for recovery is, for the most part, a struggle to regulate cognitive and emotional functions.
      PubDate: 2016-10-13T20:31:09.504486-05:
      DOI: 10.1111/adb.12466
  • Cocaine-induced synaptic structural modification is differentially
           regulated by dopamine D1 and D3 receptors-mediated signaling pathways
    • Authors: Lei Zhang; Lu Huang, Kangrong Lu, Yutong Liu, Genghong Tu, Mengjuan Zhu, Li Ying, Jinlan Zhao, N. Liu, Fukun Guo, Lin Zhang, Lu Zhang
      Abstract: Synaptic plasticity plays a critical role in cocaine addiction. The dopamine D1 and D3 receptors differentially regulate the cocaine-induced gene expression, structural remodeling and behavioral response. However, how these two receptors coordinately mediate the ultra-structural changes of synapses after cocaine exposure and whether these changes are behaviorally relevant are still not clear. Here, using quantitative electron microscopy, we show that D1 and D3 receptors have distinct roles in regulating cocaine-induced ultra-structural changes of synapses in the nucleus accumbens and caudoputamen. Pre-treatment of cocaine-treated mice with D3 receptor antagonist NGB2904 resulted in an increase in the ratio of total and asymmetric synapse to neuron and in the length of postsynaptic densities, compared with cocaine treatment alone. In contrast, pre-treatment of cocaine-treated mice with D1 receptor antagonist SCH23390 caused a reduction in synapse-to-neuron ratio and in postsynaptic densities length. Similarly, NGB2904 and SCH23390 showed opposite/differential effects on cocaine-induced structural plasticity, conditioned place preference and locomotor activity and signaling activation, including the activation of ERK, CREB and NR1 and the expression of c-fos and Cdk5. Therefore, we provide direct electron microscopy evidence that dopamine D1 and D3 receptors reciprocally regulate the ultra-structural changes of synapses following chronic exposure to cocaine. In addition, our data suggest that D1 and D3 receptors may regulate cocaine-induced ultra-structural changes and behavior responses by impact on structural plasticity and signaling transduction.By using the unbiased quantitative stereological physical dissector method, we provide direct electron microscopy evidence that dopamine D1 and D3 receptors reciprocally regulate the ultra-structural changes of synapses following chronic exposure to cocaine. In addition, our data suggest that D1 and D3 receptors may regulate cocaine-induced ultra-structural changes and behavior responses by impact on structural plasticity and signaling transduction.
      PubDate: 2016-10-12T20:05:37.016132-05:
      DOI: 10.1111/adb.12462
  • Impairment of opiate-mediated behaviors by the selective TRPV1 antagonist
    • Authors: Shi-Xun Ma; Seung-Hwan Kwon, Jee-Yeon Seo, Ji-Young Hwang, Sa-Ik Hong, Hyoung-Chun Kim, Seok-Yong Lee, Choon-Gon Jang
      Abstract: Transient receptor potential vanilloid type 1 (TRPV1), the archetypal member of the vanilloid TRP family, was initially identified as the receptor for capsaicin, the pungent ingredient in hot chili peppers. We previously demonstrated that TRPV1 in the dorsal striatum significantly contributes to morphine reward by using the conditioned place preference paradigm in mice; however, it is unknown whether TRPV1 has the same effect in other reward models. In this study, we investigated the role of TRPV1 in morphine reward by using a self-administration paradigm in rats. We found that treatment with a selective TRPV1 antagonist, SB366791, significantly decreased morphine self-administration on a fixed-ratio 1 schedule or a progressive ratio schedule of reinforcement. In addition, treatment with another selective TRPV1 antagonist, AMG9810, not only significantly prevented morphine self-administration but also prevented morphine-induced c-fos expression in the nucleus accumbens. Furthermore, administration of SB366791 decreased an anxiolytic-like effect during the morphine abstinence period. Moreover, treatment with SB366791 significantly decreased morphine-priming reinstatement. Taken together, our findings suggest that blockade of TRPV1 receptors could provide an approach to limiting morphine addiction.We found that treatment with a selective TRPV1 antagonist, SB366791, significantly decreased morphine self-administration on a fixed-ratio 1 schedule or a progressive ratio schedule of reinforcement. In addition, treatment with another selective TRPV1 antagonist, AMG9810, not only significantly prevented morphine self-administration but also prevented morphine-induced c-fos expression in the nucleus accumbens. Furthermore, administration of SB366791 decreased an anxiolytic-like effect during the morphine abstinence period. Moreover, treatment with SB366791 significantly decreased morphine-priming reinstatement.
      PubDate: 2016-10-11T21:01:01.571667-05:
      DOI: 10.1111/adb.12460
  • Gender differences in the inflammatory cytokine and chemokine profiles
           induced by binge ethanol drinking in adolescence
    • Authors: María Pascual; Jorge Montesinos, Miguel Marcos, Jorge-Luis Torres, Pilar Costa-Alba, Francisco García-García, Francisco-Javier Laso, Consuelo Guerri
      Abstract: Heavy binge drinking in adolescence can cause long-term cognitive and behavioral dysfunctions. Recent experimental evidence indicates the participation of immune system activation in the effects of ethanol in the adolescent brain and suggests gender differences. The present study aims to assess plasma cytokine and chemokine levels in male and female adolescents and young adults during acute alcohol intoxication and to correlate these results with the toll-like receptor 4 (TLR4) response. The potential role of the TLR4 signaling response was also assessed in plasma and prefrontal cortex (PFC) of adolescent wild-type and TLR4-knockout male and female mice with binge ethanol treatment. The results showed that alcohol intoxication increased the plasma levels of several cytokine and chemokine [interferon-γ, interleukin (IL)-10, IL-17A, IL-1β, IL-2, IL-4, IL-6, IL-8, fractalkine, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1α (MIP-1α)] and the upregulation of TLR4 mRNA levels occurred in intoxicated females, while elevation of colony-stimulating factor was only observed in the plasma of males. In wild-type female adolescent mice, intermittent ethanol treatment increased the levels of several cytokines (IL-17A and IL-1β) and chemokines (MCP-1, MIP-1α and fractalkine) in PFC and in serum (IL-17A, MCP-1 and MIP-1α), but significant differences in the fractalkine levels in PFC were observed only in male mice. No changes in serum or prefrontal cortex cytokine and chemokine levels were noted in ethanol-treated male or female TLR4-knockout mice. Our findings revealed that females are more vulnerable than males to inflammatory effects of binge ethanol drinking and suggested that TLR4 is an important target of ethanol-induced inflammation and neuroinflammation in adolescence.Female adolescents are more vulnerable than male adolescents to the inflammatory effects of binge alcohol drinking. Circulating cytokines and chemokines might serve as clinical biomarkers of neuroinflammation. The TLR4 response is an important target of the ethanol-induced immune and neuroimmune response in adolescence. This figure shows a negative correlation (Pearson's coefficient) between cytokines/chemokines and blood alcohol levels in intoxicated females (red ellipses) and positive correlation in intoxicated males (blue ellipses). Black and white points denote significance and tendency, respectively.
      PubDate: 2016-10-04T00:57:42.528193-05:
      DOI: 10.1111/adb.12461
  • Impaired decision-making and impulse control in Internet gaming addicts:
           evidence from the comparison with recreational Internet game users
    • Authors: Yifan Wang; Lingdan Wu, Lingxiao Wang, Yifen Zhang, Xiaoxia Du, Guangheng Dong
      Abstract: Although Internet games have been proven to be addictive, only a few game players develop online gaming addiction. A large number of players play online games recreationally without being addicted to it. These individuals are defined as recreational Internet gaming users (RGU). So far, no research has investigated decision-making and impulse control in RGU. In the current study, we used delay discounting (DD) task and probabilistic discounting (PD) task to examine decision-making and impulse control in 20 healthy controls, 20 subjects with Internet gaming disorder (IGD) and 23 RGU during fMRI scanning. At the behavioral level, RGU showed lower DD rate and higher PD rate than subjects with IGD and there was no significant difference between RGU and healthy controls on the DD and PD rates. At the neural level, RGU showed increased neural response in the parahippocampal gyrus, the anterior cingulate cortex, the medial frontal gyrus and the inferior frontal gyrus as compared with subjects with IGD. These brain regions may play an important role in preventing RGU from developing addiction. The results suggest that the RGU are capable of inhibiting impulse due to additional cognitive endeavor and the subjects with IGD have deficit in decision-making and impulsive control, which are associated with brain dysfunction.During the delay discounting and probabilistic discounting tasks, the Internet gaming disorder is more impulsive and shows lower brain activation in the parahippocampal gyrus, anterior cingulate cortex, inferior frontal gyrus, and medial frontal gyrus than recreational Internet gaming users. The results suggest that the recreational Internet gaming users are capable to inhibit impulse due to additional cognitive endeavor, and the Internet gaming disorder has deficit indecision-making and impulsive control. The brain regions are involved in decision-making and cognitive control and may be a key mechanism preventing recreational game players from the risk of developing addiction.
      PubDate: 2016-09-30T01:30:48.541869-05:
      DOI: 10.1111/adb.12458
  • Emotional, physical and sexual abuse are associated with a heightened
           limbic response to cocaine cues
    • Authors: Paul S. Regier; Zachary A. Monge, Teresa R. Franklin, Reagan R. Wetherill, Anne Teitelman, Kanchana Jagannathan, Jesse J. Suh, Ze Wang, Kimberly A. Young, Michael Gawrysiak, Daniel D. Langleben, Kyle M. Kampman, Charles P. O'Brien, Anna Rose Childress
      Abstract: Drug-reward cues trigger motivational circuitry, a response linked to drug-seeking in animals and in humans. Adverse life events have been reported to increase sensitivity to drug rewards and to bolster drug reward signaling. Therefore, we hypothesized that cocaine-dependent individuals with prior emotional, physical and sexual abuse might have a heightened mesolimbic brain response to cues for drug reward in a new brief-cue probe. Cocaine-dependent human individuals (N = 68) were stabilized in an inpatient setting and then completed an event-related blood-oxygen-level dependent functional magnetic resonance imaging task featuring 500-ms evocative (cocaine, sexual, aversive) and comparator (neutral) cues. Responses to three questions about emotional, physical and sexual abuse from the Addiction Severity Index were used to divide the patients into subgroups (history of Abuse [n = 40] versus No Abuse [n = 28]). When subjects were grouped by the historical presence or absence of emotional, physical or sexual abuse, the Abuse group showed a heightened midbrain, thalamic, caudate, and caudal orbitofrontal cortex response to cocaine cues; a similar result was found in other evocative cues, as well. These findings are the first reported for a 500-ms cocaine-cue probe, and they highlight the ability of very brief evocative cues to activate the brain's motivational circuitry. Although all participants had severe cocaine use disorders, individuals reporting prior abuse had a heightened mesolimbic response to evocative cues. To our knowledge, this is the first study in humans linking a history of abuse to a brain vulnerability (heightened mesolimbic response to drug cues) previously shown to contribute to drug-seeking.Even though all participants had severe cocaine disorders, individuals with a history of emotional, physical, and/or sexual abuse exhibited a heightened mesolimbic response to cocaine cues compared with those without a history of abuse.
      PubDate: 2016-09-22T02:10:29.85152-05:0
      DOI: 10.1111/adb.12445
  • A hypo-status in drug-dependent brain revealed by multi-modal MRI
    • Authors: Ze Wang; Jesse Suh, Dingna Duan, Stefanie Darnley, Ying Jing, Jian Zhang, Charles O'Brien, Anna Rose Childress
      Abstract: Drug addiction is a chronic brain disorder with no proven effective cure. Assessing both structural and functional brain alterations by using multi-modal, rather than purely unimodal imaging techniques, may provide a more comprehensive understanding of the brain mechanisms underlying addiction, which in turn may facilitate future treatment strategies. However, this type of research remains scarce in the literature. We acquired multi-modal magnetic resonance imaging from 20 cocaine-addicted individuals and 19 age-matched controls. Compared with controls, cocaine addicts showed a multi-modal hypo-status with (1) decreased brain tissue volume in the medial and lateral orbitofrontal cortex (OFC); (2) hypo-perfusion in the prefrontal cortex, anterior cingulate cortex, insula, right temporal cortex and dorsolateral prefrontal cortex and (3) reduced irregularity of resting state activity in the OFC and limbic areas, as well as the cingulate, visual and parietal cortices. In the cocaine-addicted brain, larger tissue volume in the medial OFC, anterior cingulate cortex and ventral striatum and smaller insular tissue volume were associated with higher cocaine dependence levels. Decreased perfusion in the amygdala and insula was also correlated with higher cocaine dependence levels. Tissue volume, perfusion, and brain entropy in the insula and prefrontal cortex, all showed a trend of negative correlation with drug craving scores. The three modalities showed voxel-wise correlation in various brain regions, and combining them improved patient versus control brain classification accuracy. These results, for the first time, demonstrate a comprehensive cocaine-dependence and craving-related hypo-status regarding the tissue volume, perfusion and resting brain irregularity in the cocaine-addicted brain.Brain atrophy (hot), hypoperfusion (violet), and hypoentropy (green) patterns in cocaine patients.
      PubDate: 2016-09-22T00:40:43.172718-05:
      DOI: 10.1111/adb.12459
  • Medications development for the treatment of alcohol use disorder:
           insights into the predictive value of animal and human laboratory models
    • Authors: Megan M. Yardley; Lara A. Ray
      Pages: 581 - 615
      Abstract: Development of effective treatments for alcohol use disorder (AUD) represents an important public health goal. This review provides a summary of completed preclinical and clinical studies testing pharmacotherapies for the treatment of AUD. We discuss opportunities for improving the translation from preclinical findings to clinical trial outcomes, focusing on the validity and predictive value of animal and human laboratory models of AUD. Specifically, while preclinical studies of medications development have offered important insights into the neurobiology of the disorder and alcohol's molecular targets, limitations include the lack of standardized methods and streamlined processes whereby animal studies can readily inform human studies. Behavioral pharmacology studies provide a less expensive and valuable opportunity to assess the feasibility of a pharmacotherapy prior to initiating larger scale clinical trials by providing insights into the mechanism of the drug, which can then inform recruitment, analyses, and assessments. Summary tables are provided to illustrate the wide range of preclinical, human laboratory, and clinical studies of medications development for alcoholism. Taken together, this review highlights the challenges associated with animal paradigms, human laboratory studies, and clinical trials with the overarching goal of advancing treatment development and highlighting opportunities to bridge the gap between preclinical and clinical research.The primary goal of this paper was to provide a perspective on medications development for alcohol use disorder along with an illustrative review of the literature encompassing preclinical, human laboratory, and clinical trials. This review highlights the marked need for standardization of testing procedures at each level of medications development, including standard protocols for experimental paradigms, population characteristics (in both animal and human studies), and analyses of predefined primary and secondary outcomes. Such standardization would allow us to more effectively integrate results from various studies using both critical reviews of the literature as well as quantitative studies and advance treatment development in this area.
      PubDate: 2016-02-01T03:59:50.678928-05:
      DOI: 10.1111/adb.12349
  • Loss of δ-GABAA receptor-mediated tonic currents in the adult prelimbic
           cortex following adolescent alcohol exposure
    • Authors: Samuel W. Centanni; Elizabeth J. Burnett, Heather Trantham-Davidson, L. Judson Chandler
      Pages: 616 - 628
      Abstract: Delayed maturation of the adolescent prefrontal cortex may render it particularly vulnerable to insults, including those associated with drugs of abuse. Using a rat model of binge alcohol exposure, the present study examined the effect of adolescent intermittent ethanol (AIE) exposure during postnatal days 28–42 on γ-aminobutyric acid (GABA)ergic neurotransmission in the prelimbic cortex. In control rats, patch-clamp electrophysiology in acute slices obtained at different postnatal ages revealed a developmental increase in the GABAA receptor-mediated tonic current in layer V pyramidal neurons but no change in layers II/III when measured in the adult. In slices from AIE-exposed rats, the amplitude of the tonic current was significantly reduced compared with controls when tested at postnatal days 45, 60 and 90–120. This AIE-induced reduction in tonic current was found to reflect attenuation of currents mediated by δ-subunit containing receptors. Consistent with this, facilitation of the tonic current by bath application of either ethanol or allopregnanolone was attenuated in slices from AIE-exposed adult rats compared with control rats. However, expression of this facilitation as a percent of the amplitude of the total current mediated by δ-GABAA receptors revealed that AIE did not alter their sensitivity to either agonist. Lastly, immunohistochemistry and Western blot analysis revealed no change in the expression of δ-GABAA subunits or their surface expression. Taken together, these studies reveal that AIE exposure results in persistent deficits in δ-GABAA tonic currents in the adult prelimbic cortex that may contribute to deficits in decision-making and behavioral control in adulthood.The adolescent prefrontal cortex (PFC) is particularly vulnerable to developmental insults from alcohol abuse. Using a rat model of adolescent alcohol exposure, the present study examined the effect of adolescent alcohol exposure on GABAergic neurotransmission in the adult PFC. We show that adult rats exposed to alcohol during adolescence exhibit prolonged deficits in tonic GABAergic currents. These observations may contribute to deficits in decision-making and behavioral control in adulthood.
      PubDate: 2016-01-24T21:41:34.523276-05:
      DOI: 10.1111/adb.12353
  • Cocaine craving during protracted withdrawal requires PKCε priming
           within vmPFC
    • Authors: Bailey W. Miller; Melissa G. Wroten, Arianne D. Sacramento, Hannah E. Silva, Christina B. Shin, Philip A. Vieira, Osnat Ben-Shahar, Tod E. Kippin, Karen K. Szumlinski
      Pages: 629 - 639
      Abstract: In individuals with a history of drug taking, the capacity of drug-associated cues to elicit indices of drug craving intensifies or incubates with the passage of time during drug abstinence. This incubation of cocaine craving, as well as difficulties with learning to suppress drug-seeking behavior during protracted withdrawal, are associated with a time-dependent deregulation of ventromedial prefrontal cortex (vmPFC) function. As the molecular bases for cocaine-related vmPFC deregulation remain elusive, the present study assayed the consequences of extended access to intravenous cocaine (6 hours/day; 0.25 mg/infusion for 10 day) on the activational state of protein kinase C epsilon (PKCε), an enzyme highly implicated in drug-induced neuroplasticity. The opportunity to engage in cocaine seeking during cocaine abstinence time-dependently altered PKCε phosphorylation within vmPFC, with reduced and increased p-PKCε expression observed in early (3 days) and protracted (30 days) withdrawal, respectively. This effect was more robust within the ventromedial versus dorsomedial PFC, was not observed in comparable cocaine-experienced rats not tested for drug-seeking behavior and was distinct from the rise in phosphorylated extracellular signal-regulated kinase observed in cocaine-seeking rats. Further, the impact of inhibiting PKCε translocation within the vmPFC using TAT infusion proteins upon cue-elicited responding was determined and inhibition coinciding with the period of testing attenuated cocaine-seeking behavior, with an effect also apparent the next day. In contrast, inhibitor pretreatment prior to testing during early withdrawal was without effect. Thus, a history of excessive cocaine taking influences the cue reactivity of important intracellular signaling molecules within the vmPFC, with PKCε playing a critical role in the manifestation of cue-elicited cocaine seeking during protracted drug withdrawal.Incubated cocaine-craving during protracted withdrawal in rats was associated with time-dependent changes in protein kinase C (PKC) epsilon priming within the ventromedial aspect of the prefrontal cortex (vmPFC). The local infusion of an inhibitor of PKC epsilon translocation blocked cue-elicited drug-seeking during later, but not earlier, withdrawal. These data argue an important role for PKC epsilon-dependent signaling within vmPFC for heightened craving during protracted cocaine withdrawal.
      PubDate: 2016-01-14T20:53:23.591267-05:
      DOI: 10.1111/adb.12354
  • Central administration of the anorexigenic peptide neuromedin U decreases
           alcohol intake and attenuates alcohol-induced reward in rodents
    • Authors: Daniel Vallöf; Lisa Ulenius, Emil Egecioglu, Jörgen A. Engel, Elisabet Jerlhag
      Pages: 640 - 651
      Abstract: By investigating the neurochemical mechanisms through which alcohol activates the brain reward systems, novel treatment strategies for alcohol use disorder (AUD), a chronic relapsing disease, can be developed. In contrast to the common view of the function of gut–brain peptides, such as neuromedin U (NMU), to regulate food intake and appetite, a novel role in reinforcement mediation has been implied. The anorexigenic effects of NMU are mediated via NMU2 receptors, preferably in the arcuate nucleus and paraventricular nucleus. The expression of NMU2 receptors is also expressed in several reward-related areas in the brain, suggesting a role in reward regulation. The present experiments were therefore set up to investigate the effect of intracerebroventricular administration of NMU on alcohol-mediated behaviors in rodents. We found that central administration of NMU attenuated alcohol-induced locomotor stimulation, accumbal dopamine release and the expression of conditioned place preference in mice. In addition, NMU dose dependently decreased alcohol intake in high, but not in low, alcohol-consuming rats. Central NMU administration did not alter the blood alcohol concentrations nor change the corticosterone levels in rodents. Given that AUD is a major health-care challenge causing an enormous cost to society and novel treatment strategies are warranted, our data suggest that NMU analogues deserve to be evaluated as novel treatment of AUD in humans.In contrast to the common view of the function of gut–brain peptides, such as neuromedin U (NMU), to regulate food intake, a novel role in reinforcement mediation has been implied. We found that central administration of NMU attenuated alcohol-induced locomotor stimulation, accumbal dopamine release and conditioned place preference as well as decreased alcohol intake in rodents. Our data suggest that NMU analogues deserve to be evaluated as novel treatment of alcohol use disorder, a major health-care challenge, in humans.
      PubDate: 2016-01-14T20:44:02.839775-05:
      DOI: 10.1111/adb.12355
  • Potentiation of amygdala AMPA receptor activity selectively promotes
           escalated alcohol self-administration in a CaMKII-dependent manner
    • Authors: Reginald Cannady; Kristen R. Fisher, Caitlin Graham, Jesse Crayle, Joyce Besheer, Clyde W. Hodge
      Pages: 652 - 664
      Abstract: Growing evidence indicates that drugs of abuse gain control over the individual by usurping glutamate-linked mechanisms of neuroplasticity in reward-related brain regions. Accordingly, we have shown that glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activity in the amygdala is required for the positive reinforcing effects of alcohol, which underlie the initial stages of addiction. It is unknown, however, if enhanced AMPAR activity in the amygdala facilitates alcohol self-administration, which is a kernel premise of glutamate hypotheses of addiction. Here, we show that low-dose alcohol (0.6 g/kg/30 minutes) self-administration increases phosphorylation (activation) of AMPAR subtype GluA1 S831 (pGluA1 S831) in the central amygdala (CeA), basolateral amygdala and nucleus accumbens core (AcbC) of selectively bred alcohol-preferring P-rats as compared with behavior-matched (non-drug) sucrose controls. The functional role of enhanced AMPAR activity was assessed via site-specific infusion of the AMPAR positive modulator, aniracetam, in the CeA and AcbC prior to alcohol self-administration. Intra-CeA aniracetam increased alcohol-reinforced but not sucrose-reinforced responding and was ineffective following intra-AcbC infusion. Because GluA1 S831 is a Ca2+/calmodulin-dependent protein kinase II (CaMKII) substrate, we sought to determine if AMPAR regulation of enhanced alcohol self-administration is dependent on CaMKII activity. Intra-CeA infusion of the cell-permeable CaMKII peptide inhibitor myristolated autocamtide-2-related inhibitory peptide (m-AIP) dose-dependently reduced alcohol self-administration. A subthreshold dose of m-AIP also blocked the aniracetam-induced escalation of alcohol self-administration, demonstrating that AMPAR-mediated potentiation of alcohol reinforcement requires CaMKII activity in the amygdala. Enhanced activity of plasticity-linked AMPAR-CaMKII signaling in the amygdala may promote escalated alcohol use via increased positive reinforcement during the initial stages of addiction.Growing evidence indicates that drugs of abuse gain control over the individual by usurping glutamate-linked mechanisms of neuroplasticity in reward-related brain regions. Here, we show that low-dose alcohol self-administration increases phosphorylation (activation) of AMPAR subtype GluA1 S831 in rat central amygdala and that CaMKII-dependent activation of AMPA receptors in the amygdala increases the positive reinforcing effects of alcohol. Enhanced activity of plasticity-linked AMPAR-CaMKII signaling may promote escalated alcohol use via increased positive reinforcement during the initial stages of addiction.
      PubDate: 2016-01-06T20:21:47.367496-05:
      DOI: 10.1111/adb.12357
  • Anaplastic lymphoma kinase regulates binge-like drinking and dopamine
           receptor sensitivity in the ventral tegmental area
    • Authors: John W. Dutton; Hu Chen, Chang You, Mark S. Brodie, Amy W. Lasek
      Pages: 665 - 678
      Abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase associated with alcohol dependence in humans and behavioral responses to ethanol in mice. To characterize the ability of ALK to control ethanol consumption, we treated mice with the ALK inhibitors TAE684 or alectinib before testing them for binge-like drinking using the drinking in the dark protocol. Mice treated with ALK inhibitors drank less ethanol than controls. In addition, TAE684 treatment abolished ethanol conditioned place preference, indicating that ALK regulates the rewarding properties of ethanol. Because the ventral tegmental area (VTA) is a key brain region involved in the rewarding effects of ethanol, we determined if Alk expression in the VTA is important for binge-like ethanol consumption. Mice expressing a short hairpin ribonucleic acid targeting Alk in the VTA drank less ethanol compared with controls. ALK is expressed on dopamine (DA) neurons in the VTA, suggesting that ALK might regulate their firing properties. Extracellular recordings of putative DA neurons in VTA slices demonstrated that ALK inhibition did not affect the ability of ethanol to stimulate, or DA to inhibit, the firing of DA neurons. However, inhibiting ALK attenuated the time-dependent reversal of inhibition produced by moderate concentrations of DA, suggesting that ALK affects DA D2 autoreceptor (D2R) desensitization. Altered desensitization of the D2R changes the firing of DA neurons and is predicted to affect DA levels and alcohol drinking. These data support the possibility that ALK might be a novel target of pharmacotherapy for reducing excessive alcohol consumption.We tested anaplastic lymphoma kinase (ALK) inhibitors in a mouse model of binge drinking and found that ALK inhibition reduced binge-like alcohol consumption. ALK appears to act in the ventral tegmental area to regulate binge-like drinking and may affect ethanol consumption through modulation of dopamine D2 receptor activity. Our results indicate that treatment with small molecule inhibitors of ALK might be a viable therapeutic strategy to reduce binge drinking in individuals with alcohol use disorders.
      PubDate: 2016-01-11T03:21:19.034183-05:
      DOI: 10.1111/adb.12358
  • The antihypertensive drug pindolol attenuates long-term but not short-term
           binge-like ethanol consumption in mice
    • Authors: Omkar L. Patkar; Arnauld Belmer, Joan Y. Holgate, Josephine R. Tarren, Masroor R. Shariff, Michael Morgan, Matthew J. Fogarty, Mark C. Bellingham, Selena E. Bartlett, Paul M. Klenowski
      Pages: 679 - 691
      Abstract: Alcohol dependence is a debilitating disorder with current therapies displaying limited efficacy and/or compliance. Consequently, there is a critical need for improved pharmacotherapeutic strategies to manage alcohol use disorders (AUDs). Previous studies have shown that the development of alcohol dependence involves repeated cycles of binge-like ethanol intake and abstinence. Therefore, we used a model of binge–ethanol consumption (drinking-in-the-dark) in mice to test the effects of compounds known to modify the activity of neurotransmitters implicated in alcohol addiction. From this, we have identified the FDA-approved antihypertensive drug pindolol, as a potential candidate for the management of AUDs. We show that the efficacy of pindolol to reduce ethanol consumption is enhanced following long-term (12 weeks) binge–ethanol intake, compared with short-term (4 weeks) intake. Furthermore, pindolol had no effect on locomotor activity or consumption of the natural reward sucrose. Because pindolol acts as a dual beta-adrenergic antagonist and 5-HT1A/1B partial agonist, we examined its effect on spontaneous synaptic activity in the basolateral amygdala (BLA), a brain region densely innervated by serotonin and norepinephrine-containing fibres. Pindolol increased spontaneous excitatory post-synaptic current frequency of BLA principal neurons from long-term ethanol-consuming mice but not naïve mice. Additionally, this effect was blocked by the 5-HT1A/1B receptor antagonist methiothepin, suggesting that altered serotonergic activity in the BLA may contribute to the efficacy of pindolol to reduce ethanol intake following long-term exposure. Although further mechanistic investigations are required, this study demonstrates the potential of pindolol as a new treatment option for AUDs that can be fast-tracked into human clinical studies.In this study, we show that the antihypertensive drug pindolol reduces ethanol consumption in mice following long-term binge-like intake. Pindolol did not have non-specific effects on locomotor activity, ethanol sensitivity or consumption of the natural reward sucrose. We also show that pindolol reduces excitatory post-synaptic current frequency in naïve mice but increases excitatory post-synaptic current frequency in long-term ethanol consuming mice. Combined, these results demonstrate that pindolol represents a novel treatment option of the management of alcohol use disorders. Figure 1 highlights the key finding of the study.
      PubDate: 2016-01-11T03:20:03.779359-05:
      DOI: 10.1111/adb.12359
  • Intra-cerebral and intra-nasal melanocortin-4 receptor antagonist blocks
           withdrawal hyperalgesia in alcohol-dependent rats
    • Authors: Emily A. Roltsch Hellard; Renata A. Impastato, Nicholas W. Gilpin
      Pages: 692 - 701
      Abstract: Humans diagnosed with alcohol use disorder are more sensitive to painful stimuli during withdrawal, which suggests that excessive alcohol drinking worsens pain outcomes. Alcohol-dependent rats exhibit increases in nociceptive sensitivity during withdrawal. Data from animal models suggest that brain melanocortin-4 receptors (MC4Rs) mediate alcohol drinking and nociception. Here we tested: (1) the effect of alcohol dependence on thermal nociception in rats, and (2) the ability of acute alcohol and (3) MC4R antagonists to reverse hyperalgesia during withdrawal in alcohol-dependent rats. Rats were trained to self-administer operant alcohol and were tested for baseline thermal nociception. Half of the rats were made dependent on alcohol, then all rats were cannulated in the lateral ventricle. We tested the effects of acute alcohol drinking, acute fixed-dose alcohol, intra-ventricular agouti-related protein (endogenous MC4R antagonist), intra-ventricular HS014 (synthetic MC4R antagonist) and intra-nasal HS014 on hyperalgesia during withdrawal in alcohol-dependent rats, relative to non-dependent drinkers and alcohol-naïve controls. Alcohol-dependent rats exhibit thermal hyperalgesia that is abolished by alcohol drinking, bolus alcohol and intra-ventricular and intra-nasal MC4R antagonists. These manipulations did not affect thermal nociception in non-dependent drinkers and alcohol-naïve controls, suggesting that alcohol dependence produces neuroadaptations in brain MC4R systems. These results suggest that brain MC4R systems may be an effective therapeutic target for reducing nociception in the alcohol-dependent organism.Alcohol-dependent rats exhibit thermal hyperalgesia, which is abolished by alcohol drinking, bolus alcohol, and intra-ventricular and intra-nasal melanocortin 4 receptor (MC4R) antagonists. These manipulations did not affect thermal nociception in non-dependent drinkers and alcohol-naïve controls, suggesting that alcohol dependence produces neuroadaptations in brain MC4R systems. These results suggest that brain MC4R systems may be an effective therapeutic target for reducing nociception in alcohol-dependent organism.
      PubDate: 2016-01-24T21:46:12.272568-05:
      DOI: 10.1111/adb.12360
  • Oxytocin inhibits ethanol consumption and ethanol-induced dopamine release
           in the nucleus accumbens
    • Authors: Sebastian T. Peters; Michael T. Bowen, Kathrin Bohrer, Iain S. McGregor, Inga D. Neumann
      Pages: 702 - 711
      Abstract: Alcohol (EtOH) is one of the most widely abused recreational drugs and is arguably the most harmful. However, current treatment options for alcohol-use disorders generally have limited efficacy and poor uptake in the community. In this context, the neuropeptide oxytocin (OXT) has emerged as a promising potential treatment option for a number of substance-use disorders, including alcoholism. The utility of OXT in reducing consumption of and craving for a wide range of substances may lie in its ability to modulate drug-induced neurochemical effects within the mesolimbic dopamine pathway. However, the impact of OXT on EtOH actions in this pathway has yet to be explored. Here, we reveal that an acute intracerebroventricular (icv) infusion of OXT (1 µg/5 µl) attenuated voluntary EtOH (20 percent) self-administration after chronic intermittent access to EtOH for 59 days (28 drinking sessions) in male Wistar rats. Next, we demonstrated that an acute intraperitoneal (ip) injection of EtOH (1.5 g/kg, 15 percent w/v) increased dopamine release within the nucleus accumbens in both EtOH-naive rats and rats that had received 10 daily ip injections of EtOH. Icv OXT completely blocked the EtOH-induced dopamine release in both EtOH-naive and chronically treated rats. The attenuation of EtOH-induced dopamine release by OXT may help to explain the reduced EtOH self-administration observed following icv OXT infusion.
      PubDate: 2016-01-25T20:45:33.561908-05:
      DOI: 10.1111/adb.12362
  • Adult rat cortical thickness changes across age and following adolescent
           intermittent ethanol treatment
    • Authors: Ryan P. Vetreno; Richard Yaxley, Beatriz Paniagua, G. Allan Johnson, Fulton T. Crews
      Pages: 712 - 723
      Abstract: Human studies have established that adolescence is a period of brain maturation that parallels the development of adult behaviors. However, little is known regarding cortical development in the adult rat brain. We used magnetic resonance imaging (MRI) and histology to assess the impact of age on adult Wistar rat cortical thickness on postnatal day (P)80 and P220 as well as the effect of adolescent binge ethanol exposure on adult (P80) cortical thickness. MRI revealed changes in cortical thickness between P80 and P220 that differ across cortical region. The adult P220 rat prefrontal cortex increased in thickness whereas cortical thinning occurred in both the cingulate and parietal cortices relative to young adult P80 rats. Histological analysis confirmed the age-related cortical thinning. In the second series of experiments, an animal model of adolescent intermittent ethanol (AIE; 5.0 g/kg, intragastrically, 20 percent ethanol w/v, 2 days on/2 days off from P25 to P55) was used to assess the effects of alcohol on cortical thickness in young adult (P80) rats. MRI revealed that AIE resulted in region-specific cortical changes. A small region within the prefrontal cortex was significantly thinner whereas medial cortical regions were significantly thicker in young adult (P80) AIE-treated rats. The observed increase in cortical thickness was confirmed by histology. Thus, the rat cerebral cortex continues to undergo cortical thickness changes into adulthood, and adolescent alcohol exposure alters the young adult cortex that could contribute to brain dysfunction in adulthood.Magnetic resonance imaging and histology was used to determine the effect of ageing and adolescent binge ethanol exposure on cortical thickness in adult rats. We discovered that the cerebral cortex continues to undergo age-associated cortical thinning and expansion into adulthood, which was altered by prior adolescent binge ethanol exposure. These data reveal that the cerebral cortex continues to undergo refinement into adulthood and that adolescent binge ethanol treatment alters adult cortical thickness that might contribute to behavioural dysfunction.
      PubDate: 2016-02-01T03:41:13.81813-05:0
      DOI: 10.1111/adb.12364
  • Oleoylethanolamide prevents neuroimmune HMGB1/TLR4/NF-kB danger signaling
           in rat frontal cortex and depressive-like behavior induced by ethanol
           binge administration
    • Authors: María Antón; Francisco Alén, Raquel Gómez de Heras, Antonia Serrano, Francisco Javier Pavón, Juan Carlos Leza, Borja García-Bueno, Fernando Rodríguez de Fonseca, Laura Orio
      Pages: 724 - 741
      Abstract: Alcohol abuse is frequently characterized by a specific pattern of intake in binge drinking episodes, inducing neuroinflammation and brain damage. Here, we characterized the temporal profile of neuroinflammation in rats exposed to intragastric binge ethanol administrations (3 times/day × 4 days) and tested the anti-inflammatory/neuroprotective properties of the satiety factor oleoylethanolamide (OEA). Pre-treatment with OEA (5 mg/kg, i.p.) previous each alcohol gavage blocked the expression of high mobility group box 1 (HMGB1) danger signal and the innate immunity Toll-like receptors 4 (TLR4) in frontal cortex, and inhibited the nuclear factor-kappa B (NF-kB) proinflammatory cascade induced by alcohol binge administration. OEA reduced the levels of interleukin-1beta (IL-1β), the monocyte chemoattractant protein-1 (MCP-1), and the enzymes cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in ethanol binged animals. Elevations in plasma tumor necrosis factor alpha (TNF-α) and IL-1β after ethanol were also inhibited by OEA. OEA also prevented ethanol-induced lipid peroxidation, caspase-8 and pro-apoptotic caspase-3 activation in frontal cortex. Additionally, OEA blocked the rise in blood corticosterone levels after ethanol with no alteration in blood ethanol levels and may affect ethanol-induced gut permeability for endotoxin. Finally, OEA, administered as a pre-treatment during the ethanol binge, exerted antidepressant-like effects during acute withdrawal. Altogether, results highlight a beneficial profile of OEA as a potent anti-inflammatory, antioxidant, neuroprotective and antidepressant-like compound to treat alcohol abuse.In this study, we reported a beneficial role for the lipid oleoylethanolamide (OEA) to treat alcohol binge drinking because of its antiinflammatory, antioxidant, neuroprotective and antidepressant-like effects. Pre-treatment with OEA during binging episodes blocked the expression of HMGB1/TLR4 cell danger signaling and inhibited the nuclear factor-kappa B-related cascade of proinflammatory mediators, affording protection against ethanol-induced lipid peroxidation and apoptosis in frontal cortex. Additionally, OEA blocked the rise in blood corticosterone induced by alcohol binge and had antidepressant-like actions during early withdrawal.
      PubDate: 2016-02-09T01:33:31.350686-05:
      DOI: 10.1111/adb.12365
  • Cannabidiol disrupts the reconsolidation of contextual drug-associated
           memories in Wistar rats
    • Authors: Cristiane Ribeiro Carvalho; Reinaldo Naoto Takahashi
      Pages: 742 - 751
      Abstract: In addicts, craving and relapse are frequently induced by the recall of memories related to a drug experience. Several studies have demonstrated that drug-related memories are reactivated after exposure to environmental cues and may undergo reconsolidation, a process that can strengthen memories. Thus, reactivation of mnemonic traces provides an opportunity for disrupting memories that contribute to the pathological cycle of addiction. Here we used drug-induced conditioned place preference (CPP) to investigate whether cannabidiol (CBD), a phytocannabinoid, given just after reactivation sessions, would affect reconsolidation of drug-reward memory, reinstatement of morphine-CPP, or conditioned place aversion precipitated by naltrexone in Wistar rats. We found that CBD impaired the reconsolidation of preference for the environment previously paired with both morphine and cocaine. This disruption seems to be persistent, as the preference did not return after further reinstatement induced by priming drug and stress reinstatement. Moreover, in an established morphine-CPP, an injection of CBD after the exposure to a conditioning session led to a significant reduction of both morphine-CPP and subsequent conditioned place aversion precipitated by naltrexone in the same context. Thus, established memories induced by a drug of abuse can be blocked after reactivation of the drug experience. Taken together, these results provide evidence for the disruptive effect of CBD on reconsolidation of contextual drug-related memories and highlight its therapeutic potential to attenuate contextual memories associated with drugs of abuse and consequently to reduce the risk of relapse.This study examines the effects of an acute injection of cannabidiol (CBD) post-reactivation on reconsolidation of drug associated memories in rats. CBD persistently disrupts the reconsolidation of morphine-CPP and suppresses subsequent morphine-CPA to the same context (see figure). Our findings suggest CBD may be a potentially pharmacologic adjunct to cue exposure cognitive behavior therapy used for developing novel treatments for weakening memories induced by drugs of abuse and subsequently reducing the risk of withdrawal and relapse.
      PubDate: 2016-02-01T04:05:20.763871-05:
      DOI: 10.1111/adb.12366
  • Expression of functional cannabinoid CB2 receptor in VTA dopamine neurons
           in rats
    • Authors: Hai-Ying Zhang; Ming Gao, Hui Shen, Guo-Hua Bi, Hong-Ju Yang, Qing-Rong Liu, Jie Wu, Eliot L. Gardner, Antonello Bonci, Zheng-Xiong Xi
      Pages: 752 - 765
      Abstract: We have recently reported the expression of functional cannabinoid CB2 receptors (CB2Rs) in midbrain dopamine (DA) neurons in mice. However, little is known whether CB2Rs are similarly expressed in rat brain because significant species differences in CB2R structures and expression are found. In situ hybridization and immunohistochemical assays detected CB2 gene and receptors in DA neurons of the ventral tegmental area (VTA), which was up-regulated in cocaine self-administration rats. Electrophysiological studies demonstrated that activation of CB2Rs by JWH133 inhibited VTA DA neuronal firing in single dissociated neurons. Systemic administration of JWH133 failed to alter, while local administration of JWH133 into the nucleus accumbens inhibited cocaine-enhanced extracellular DA and i.v. cocaine self-administration. This effect was blocked by AM630, a selective CB2R antagonist. These data suggest that CB2Rs are expressed in VTA DA neurons and functionally modulate DA neuronal activities and cocaine self-administration behavior in rats.The presence of neuronal CB2 receptor in the brain has been controversial. The present study provides convincing evidence demonstrating that CB2 gene (mRNA) and receptors are not only expressed in midbrain dopamine neurons, but also functionally modulate dopamine neuronal excitability, striatal dopamine release and intravenous cocaine self-administration. In addition, cocaine self-administration up-regulates CB2 gene expression in dopamine neurons, suggesting that brain CB2 receptor may constitute a new target in medication development for treatment of addiction or other dopamine-related central nervous system disorders.
      PubDate: 2016-02-01T03:15:53.835503-05:
      DOI: 10.1111/adb.12367
  • Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission
           in the rat basolateral amygdala
    • Authors: Florence P. Varodayan; Michal Bajo, Neeraj Soni, George Luu, Samuel G. Madamba, Paul Schweitzer, Marisa Roberto
      Pages: 766 - 778
      Abstract: The basolateral nucleus of the amygdala (BLA) is critical to the pathophysiology of anxiety-driven alcohol drinking and relapse. The endogenous cannabinoid/type 1 cannabinoid receptor (eCB/CB1) system curbs BLA-driven anxiety and stress responses via a retrograde negative feedback system that inhibits neurotransmitter release, and BLA CB1 activation reduces GABA release and drives anxiogenesis. Additionally, decreased amygdala CB1 is observed in abstinent alcoholic patients and ethanol withdrawn rats. Here, we investigated the potential disruption of eCB/CB1 signaling on GABAergic transmission in BLA pyramidal neurons of rats exposed to 2–3 weeks intermittent ethanol. In the naïve rat BLA, the CB1 agonist WIN 55,212-2 (WIN) decreased GABA release, and this effect was prevented by the CB1 antagonist AM251. AM251 alone increased GABA release via a mechanism requiring postsynaptic calcium-dependent activity. This retrograde tonic eCB/CB1 signaling was diminished in chronic ethanol exposed rats, suggesting a functional impairment of the eCB/CB1 system. In contrast, acute ethanol increased GABAergic transmission similarly in naïve and chronic ethanol exposed rats, via both presynaptic and postsynaptic mechanisms. Notably, CB1 activation impaired ethanol's facilitation of GABAergic transmission across both groups, but the AM251-induced and ethanol-induced facilitation of GABA release was additive, suggesting independent presynaptic sites of action. Collectively, the present findings highlight a critical CB1 influence on BLA GABAergic transmission that is dysregulated by chronic ethanol exposure and, thus, may contribute to the alcohol-dependent state.Endogenous cannabinoid/type 1 cannabinoid receptor (eCB/CB1) signaling modulates basolateral nucleus of the amygdala (BLA) GABA release, a mechanism critical for anxiety-driven alcohol drinking and relapse. Our electrophysiological results show that BLA GABA release was increased by CB1 activation and decreased by CB1 blockade; chronic ethanol exposure blunted these effects, suggesting a functional impairment of eCB/CB1 signaling. Also, CB1 blockade and acute ethanol increased GABA release in an additive manner, suggesting that they have different presynaptic sites of action.
      PubDate: 2016-01-20T00:23:37.233281-05:
      DOI: 10.1111/adb.12369
  • Topiramate and motivational enhancement therapy for cannabis use among
           youth: a randomized placebo-controlled pilot study
    • Authors: Robert Miranda; Hayley Treloar, Alexander Blanchard, Alicia Justus, Peter M. Monti, Thomas Chun, Robert Swift, Jennifer W. Tidey, Chad J. Gwaltney
      Pages: 779 - 790
      Abstract: Cannabis misuse accounts for nearly all of the substance abuse treatment admissions among youth in the United States. Most youth do not experience sustained benefit from existing psychosocial treatments; however, medication development research for treating adolescent cannabis misuse is almost nonexistent. We conducted a double-blind, placebo-controlled, pilot study to test the potential efficacy of topiramate plus motivational enhancement therapy (MET) for treating cannabis use among adolescents. Sixty-six heavy cannabis users, ages 15 to 24 years, were randomized to one of two 6-week treatment conditions: topiramate plus MET or placebo plus MET. Topiramate was titrated over 4 weeks then stabilized at 200 mg/day for 2 weeks. MET was delivered biweekly for a total of three sessions. Only 48 percent of youths randomized to topiramate completed the 6-week trial (n = 19), compared with 77 percent of youths in the placebo condition (n = 20). Adverse medication side effects were the most common reason for withdrawal among participants in the topiramate group. Latent growth models showed that topiramate was superior to placebo for reducing the number of grams smoked per use day, but it did not improve abstinence rates. The same pattern of results was found when values for missing outcomes were imputed. We show that topiramate combined with MET demonstrated efficacy for reducing how much cannabis adolescents smoked when they used but did not affect abstinence rates. The magnitude of this effect was modest, however, and topiramate was poorly tolerated by youths, which calls into question the clinical importance of these findings.Results of this double-blind, placebo-controlled pilot study showed that topiramate, combined with motivational enhancement therapy, reduced how much cannabis adolescents smoked when they used but it did not affect abstinence rates. Significant increases in abstinence rates were observed in both medication conditions. Topiramate was poorly tolerated by many youths, however, and the magnitude of its effect on cannabis use was modest, which calls to question the clinical importance of these findings.
      PubDate: 2016-01-11T03:18:23.165053-05:
      DOI: 10.1111/adb.12350
  • Activation of the ventral and dorsal striatum during cue reactivity in
           Internet gaming disorder
    • Authors: Lu Liu; Sarah W. Yip, Jin-Tao Zhang, Ling-Jiao Wang, Zi-Jiao Shen, Ben Liu, Shan-Shan Ma, Yuan-Wei Yao, Xiao-Yi Fang
      Pages: 791 - 801
      Abstract: Studies conducted in drug addiction suggest a transition in processing of drug-related cues from the ventral to the dorsal component of the striatum. However, this process has not been studied in a behavioral addiction. Assessment of this process in a non-drug addiction can provide insight into the pathophysiology of both substance and behavioral addictions. Thirty-nine male Internet gaming disorder (IGD) subjects and 23 male matched healthy controls (HCs) participated in functional magnetic resonance imaging during performance of a cue-reactivity task involving alternating presentation of Internet gaming-related stimuli (game cues) and general Internet surfing-related stimuli (control cues). Cue-induced neural activations in the ventral and dorsal striatum (DS) were compared between IGD and HC participants. Associations between cue-reactivity within these regions and cue-induced craving and severity and duration of IGD were also explored. IGD participants exhibited higher cue-induced activations within both the ventral and DS when compared with HCs. Within the IGD group, activity within the left ventral striatum (VS) was correlated negatively with cue-induced craving; positive associations were found between activations within the DS (right putamen, pallidum and left caudate) and duration of IGD. Cue-induced activity within the left putamen was negatively associated with right VS volumes among IGD participants. Consistent with studies in substance addictions, our results suggest that a transition from ventral to dorsal striatal processing may occur among individuals with IGD, a condition without the impact of substance intake.For the individuals with Internet gaming disorder (IGD), cue-induced activity within the left ventral striatum was correlated negatively with cue-induced craving, whereas positive associations were found between activations within the dorsal striatum (right putamen, pallidum, and left caudate) and duration of IGD.
      PubDate: 2016-01-05T19:59:22.611615-05:
      DOI: 10.1111/adb.12338
  • Frontostriatal circuits, resting state functional connectivity and
           cognitive control in internet gaming disorder
    • Authors: Kai Yuan; Dahua Yu, Chenxi Cai, Dan Feng, Yangding Li, Yanzhi Bi, Jixin Liu, Yi Zhang, Chenwang Jin, Linling Li, Wei Qin, Jie Tian
      Pages: 813 - 822
      Abstract: Converging evidence has identified cognitive control deficits in internet gaming disorder (IGD). Recently, mounting evidence had revealed that resting state functional connectivity (RSFC) and structural connectivity of frontostriatal circuits could modulate cognitive control in healthy individuals. Unfortunately, relatively little is known about the thoroughly circuit-level characterization of the frontostriatal pathways (both the dorsal and ventral striatum) during resting-state and their association with cognitive control in IGD. In the current study, the differences of striatum volume and RSFC networks were investigated between 43 young IGD individuals and 44 healthy controls. Meanwhile, cognitive control deficits were assessed by Stroop task performances. The neuroimaging findings were then correlated with the Stroop task behaviors. In IGD subjects, we demonstrated an increased volume of right caudate and nucleus accumbens (NAc) as well as reduced RSFC strength of dorsal prefrontal cortex (DLPFC)–caudate and orbitofrontal cortex (OFC)–NAc. NAc volumes were positively correlated with internet addiction test scores in IGD. The caudate volume and DLPFC–caudate RSFC was correlated with the impaired cognitive control (more incongruent errors in Stroop task) in IGD. Consistent with substance use disorder (SUD) findings, we detected striatum volume and frontostriatal circuits RSFC differences between IGD and healthy controls, which provided evidence of some degree of the similarity between IGD and SUD. More importantly, the cognitive control deficits in IGD were correlated with the reduced frontostrital RSFC strength. It is hoped that our results could shed insight on the neurobiological mechanisms of IGD and suggest potential novel therapeutic targets for treatment.Reduced resting-state functional connectivity between the right caudate and the right dorsolateral prefrontal cortex was negatively correlated with more errors during incongruent condition in Stroop task in IGD subjects.
      PubDate: 2016-01-14T20:42:10.406073-05:
      DOI: 10.1111/adb.12348
  • Brain reactivity to alcohol and cannabis marketing during sobriety and
    • Authors: Elizabeth B. Sousa Fernandes Perna; Eef L. Theunissen, Kim P. C. Kuypers, Elisabeth A. Evers, Peter Stiers, Stefan W. Toennes, Jurriaan Witteman, Wim Dalen, Johannes G. Ramaekers
      Pages: 823 - 832
      Abstract: Drugs of abuse stimulate striatal dopamine release and activate reward pathways. This study examined the impact of alcohol and cannabis marketing on the reward circuit in alcohol and cannabis users while sober and intoxicated. It was predicted that alcohol and cannabis marketing would increase striatal activation when sober and that reward sensitivity would be less during alcohol and cannabis intoxication. Heavy alcohol (n = 20) and regular cannabis users (n = 21) participated in a mixed factorial study involving administration of alcohol and placebo in the alcohol group and cannabis and placebo in the cannabis group. Non-drug users (n = 20) served as between group reference. Brain activation after exposure to alcohol and cannabis marketing movies was measured using functional magnetic resonance imaging and compared between groups while sober and compared with placebo while intoxicated. Implicit alcohol and cannabis cognitions were assessed by means of a single-category implicit association test. Alcohol and cannabis marketing significantly increased striatal BOLD activation across all groups while sober. Striatal activation however decreased during intoxication with alcohol and cannabis. Implicit associations with cannabis marketing cues were significantly more positive in alcohol and cannabis users as compared with non-drug using controls. Public advertising of alcohol or cannabis use elicits striatal activation in the brain's reward circuit. Reduction of marketing would reduce brain exposure to reward cues that motivate substance use. Conversely, elevated dopamine levels protect against the reinforcing potential of marketing.We examined brain reactivity to alcohol and cannabis marketing during sobriety as well as intoxication and compared brain network activation and implicit cognition during both states. Our findings suggest that alcohol and drug marketing can trigger similar brain responses to those that occur during drug use and drug craving, but the reinforcing strength of drug marketing cues appear to be reduced following alcohol and cannabis intoxication.
      PubDate: 2016-01-14T21:02:15.824246-05:
      DOI: 10.1111/adb.12351
  • Striatal activation and frontostriatal connectivity during non-drug reward
           anticipation in alcohol dependence
    • Authors: Alena Becker; Martina Kirsch, Martin Fungisai Gerchen, Falk Kiefer, Peter Kirsch
      Pages: 833 - 843
      Abstract: According to prevailing neurobiological theories of addiction, altered function in neural reward circuitry is a central mechanism of alcohol dependence. Growing evidence postulates that the ventral striatum (VS), as well as areas of the prefrontal cortex, contribute to the increased incentive salience of alcohol-associated cues, diminished motivation to pursue non-drug rewards and weakened strength of inhibitory cognitive control, which are central to addiction. The present study aims to investigate the neural response and functional connectivity underlying monetary, non-drug reward processing in alcohol dependence. We utilized a reward paradigm to investigate the anticipation of monetary reward in 32 alcohol-dependent inpatients and 35 healthy controls. Functional magnetic resonance imaging was used to measure task-related brain activation and connectivity. Alcohol-dependent patients showed increased activation of the VS during anticipation of monetary gain compared with healthy controls. Generalized psychophysiological interaction analyses revealed decreased functional connectivity between the VS and the dorsolateral prefrontal cortex in alcohol dependent patients relative to controls. Increased activation of the VS and reduced frontostriatal connectivity were associated with increased craving. These findings provide evidence that alcohol dependence is rather associated with disrupted integration of striatal and prefrontal processes than with a global reward anticipation deficit.Neurobiological theories of addiction highlight the role of the prefrontal cortex not only through its engagement in executive functions but also through monitoring the mesolimbic reward system. We investigated the neural activation and connectivity underlying non-drug reward anticipation in alcohol dependence. Alcohol-dependent patients showed increased activation of the ventral striatum, along with decreased frontostriatal connectivity, during the anticipation of monetary reward. This diminished frontostriatal connectivity was associated with increased craving, as measured by the Obsessive Compulsive Drinking Scale.
      PubDate: 2016-01-11T03:20:48.443171-05:
      DOI: 10.1111/adb.12352
  • Cocaine addiction is associated with abnormal prefrontal function,
           increased striatal connectivity and sensitivity to monetary incentives,
           and decreased connectivity outside the human reward circuit
    • Authors: Lucía Vaquero; Estela Cámara, Frederic Sampedro, José Pérez de los Cobos, Francesca Batlle, Josep Maria Fabregas, Joan Artur Sales, Mercè Cervantes, Xavier Ferrer, Gerardo Lazcano, Antoni Rodríguez-Fornells, Jordi Riba
      Pages: 844 - 856
      Abstract: Cocaine addiction has been associated with increased sensitivity of the human reward circuit to drug-related stimuli. However, the capacity of non-drug incentives to engage this network is poorly understood. Here, we characterized the functional sensitivity to monetary incentives and the structural integrity of the human reward circuit in abstinent cocaine-dependent (CD) patients and their matched controls. We assessed the BOLD response to monetary gains and losses in 30 CD patients and 30 healthy controls performing a lottery task in a magnetic resonance imaging scanner. We measured brain gray matter volume (GMV) using voxel-based morphometry and white matter microstructure using voxel-based fractional anisotropy (FA). Functional data showed that, after monetary incentives, CD patients exhibited higher activation in the ventral striatum than controls. Furthermore, we observed an inverted BOLD response pattern in the prefrontal cortex, with activity being highest after unexpected high gains and lowest after losses. Patients showed increased GMV in the caudate and the orbitofrontal cortex, increased white matter FA in the orbito-striatal pathway but decreased FA in antero-posterior association bundles. Abnormal activation in the prefrontal cortex correlated with GMV and FA increases in the orbitofrontal cortex. While functional abnormalities in the ventral striatum were inversely correlated with abstinence duration, structural alterations were not. In conclusion, results suggest abnormal incentive processing in CD patients with high salience for rewards and punishments in subcortical structures but diminished prefrontal control after adverse outcomes. They further suggest that hypertrophy and hyper-connectivity within the reward circuit, to the expense of connectivity outside this network, characterize cocaine addiction.Using a lottery task and magnetic resonance imaging, we demonstrate that cocaine-dependent patients show functional and structural brain abnormalities. While patients show hypersensitivity to incentives in subcortical regions, they fail to engage the prefrontal cortex following adverse behavioral outcomes. Structurally, they show increased gray and white matter in reward-processing areas but decreased white matter integrity in antero-posterior association bundles. These findings suggest that abnormal fronto-subcortical function, hypertrophy and hyper-connectivity within the reward circuit, and decreased connectivity outside this network, characterize cocaine addiction.
      PubDate: 2016-01-19T21:27:48.351251-05:
      DOI: 10.1111/adb.12356
  • Posterior hippocampal regional cerebral blood flow predicts abstinence: a
           replication study
    • Authors: Bryon Adinoff; Thomas S. Harris, Hong Gu, Elliot A. Stein
      Pages: 857 - 863
      Abstract: The posterior hippocampus (pHp) plays a major role in the processing and storage of drug-related cues and is linked to striatal-limbic brain circuits involved with craving and drug salience. We have recently reported that increased basal regional cerebral blood flow (rCBF) in a pHp loci, as measured by pseudo-continuous arterial spin labeling magnetic resonance imaging, predicted days to cocaine relapse following residential treatment. In this secondary analysis, we explored whether rCBF in this same pHp region would successfully predict 30-day point prevalence abstinence 60 days following residential treatment in an independent group of previously studied participants with cocaine dependence. rCBF was assessed with single photon emission computerized tomography during a saline infusion in 21 cocaine dependence and 22 healthy control participants. pHp rCBF was significantly higher in those endorsing substance use (n = 10) relative to both abstinent (n = 11) (p 
      PubDate: 2016-01-11T03:41:00.519168-05:
      DOI: 10.1111/adb.12361
  • Frontal cortex gray matter volume alterations in pathological gambling
           occur independently from substance use disorder
    • Authors: Evangelos Zois; Falk Kiefer, Tagrid Lemenager, Sabine Vollstädt-Klein, Karl Mann, Mira Fauth-Bühler
      Pages: 864 - 872
      Abstract: Neuroimaging in pathological gambling (PG) allows studying brain structure independent of pharmacological/neurotoxic effects occurring in substance addiction. Because of high comorbidity of PG with substance use disorder (SUD), first results on structural deficits in PG are controversial. The current investigation is the first to examine gray matter (GM) volume alterations in PG controlling for the impact of SUD by comparing non-comorbid (PGPURE) and two comorbid (PGALCOHOL and PGPOLY) groups. Two hundred and five individuals were included in the analysis: 107 patients diagnosed with PG and 98 healthy controls (HCs). We employed voxel-based morphometry to look for GM volume differences between the groups controlling for age, smoking and depression. GM decreases in the superior medial and orbital frontal cortex occur independently of substance use in PGPURE compared with HCs. The frontal pattern of GM decrease was comparable with PGALCOHOL group where additionally GM volume was decreased in the anterior cingulate but increased in the amygdala. Moreover, regions in PGALCOHOL + POLY with reduced GM volume were the medial frontal, anterior cingulate and occipital lobe regions. PGALCOHOL + POLY not only exhibited structural deficits in comparison with HCs but also relative to PGPURE in the precuneus and post-central gyrus. We demonstrated specific frontal cortex GM deficits in PG without SUD comorbidities. Whereas some target regions reported in earlier studies might result from comorbid substance abuse, there seems to be a core set of frontal alterations associated with addicted gambling behaviour independent of toxic substance effects.The first morphometric investigation to examine gray matter volume alterations in pathological gamblers controlling for the impact of substance use disorder by comparing non-comorbid gamblers and two comorbid groups – alcohol and polysubstance. One hundred and seven patients were included in the analysis and 98 healthy controls. We demonstrated specific frontal-cortex gray-matter deficits in gamblers with and without substance use disorder comorbidity. Those frontal alterations are associated with addicted gambling behavior independent of toxic substance effects.
      PubDate: 2016-01-15T11:15:13.006594-05:
      DOI: 10.1111/adb.12368
  • Characterization of white matter integrity deficits in cocaine-dependent
           individuals with substance-induced psychosis compared with non-psychotic
           cocaine users
    • Authors: Taylor S. Willi; Alasdair M. Barr, Kristina Gicas, Donna J. Lang, Fidel Vila-Rodriguez, Wayne Su, Allen E. Thornton, Olga Leonova, Chantelle J. Giesbrecht, Ric M. Procyshyn, Alexander Rauscher, William G. MacEwan, William G. Honer, William J. Panenka
      Pages: 873 - 881
      Abstract: With sufficient drug exposure, some individuals develop transient psychotic symptoms referred to as ‘substance-induced psychosis’ (SIP), which closely resemble the symptoms observed in schizophrenia spectrum disorders. The comparability in psychotic presentation between SIP and the schizophrenias suggests that similar underlying neural deficits may contribute to the emergence of psychosis across these disorders. Only a small number of studies have investigated structural alterations in SIP, and all have been limited to volumetric imaging methods, with none controlling for the effects of chronic drug exposure. To investigate white matter abnormalities associated with SIP, diffusion tensor imaging was employed in a group of individuals with cocaine-associated psychosis (CAP; n = 24) and a cocaine-dependent non-psychotic (CDN) group (n = 43). Tract-based spatial statistics was used to investigate group differences in white matter diffusion parameters. The CAP group showed significantly lower fractional anisotropy values than the CDN group (p 
      PubDate: 2016-02-01T03:34:53.429277-05:
      DOI: 10.1111/adb.12363
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