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Publisher: John Wiley and Sons   (Total: 1577 journals)

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Showing 1 - 200 of 1577 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 12, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 64, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 46, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 49, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 148, 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: 56, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 6, SJR: 1.69, h-index: 88)
Acta Polymerica     Hybrid Journal   (Followers: 9)
Acta Psychiatrica Scandinavica     Hybrid Journal   (Followers: 35, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 6, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 3)
Addiction     Hybrid Journal   (Followers: 35, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 13, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 26, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 26, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 50, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 256, 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: 5, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 5)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 17, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 13, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 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: 35, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 15, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 10, 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: 45, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 30, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 34, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 50, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 135, 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: 27, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 33, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 12, SJR: 1.018, h-index: 58)
American J. of Industrial Medicine     Hybrid Journal   (Followers: 16, SJR: 0.993, h-index: 85)
American J. of Medical Genetics Part A     Hybrid Journal   (Followers: 16, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 6, SJR: 2.315, h-index: 79)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 37, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 264, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 3, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 17, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 126, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 10, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 16)
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: 207)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 213, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 37, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 9, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 6, SJR: 0.569, h-index: 24)
Annalen der Physik     Hybrid Journal   (Followers: 5, SJR: 1.46, h-index: 40)
Annals of Anthropological Practice     Partially Free   (Followers: 2, SJR: 0.187, h-index: 5)
Annals of Applied Biology     Hybrid Journal   (Followers: 7, SJR: 0.816, h-index: 56)
Annals of Clinical and Translational Neurology     Open Access   (Followers: 1)
Annals of Human Genetics     Hybrid Journal   (Followers: 9, SJR: 1.191, h-index: 67)
Annals of Neurology     Hybrid Journal   (Followers: 48, 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: 13)
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: 17, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 15)
Anthropology of Consciousness     Hybrid Journal   (Followers: 11, SJR: 0.172, h-index: 5)
Anthropology of Work Review     Hybrid Journal   (Followers: 11, SJR: 0.256, h-index: 5)
Anthropology Today     Hybrid Journal   (Followers: 91, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 47, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 7, 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: 68, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 152, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 48, SJR: 0.868, h-index: 13)
Applied Stochastic Models in Business and Industry     Hybrid Journal   (Followers: 5, SJR: 0.613, h-index: 24)
Aquaculture Nutrition     Hybrid Journal   (Followers: 14, SJR: 1.025, h-index: 55)
Aquaculture Research     Hybrid Journal   (Followers: 31, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 36, SJR: 1.047, h-index: 57)
Arabian Archaeology and Epigraphy     Hybrid Journal   (Followers: 11, SJR: 0.453, h-index: 11)
Archaeological Prospection     Hybrid Journal   (Followers: 12, SJR: 0.922, h-index: 21)
Archaeology in Oceania     Hybrid Journal   (Followers: 13, SJR: 0.745, h-index: 18)
Archaeometry     Hybrid Journal   (Followers: 27, SJR: 0.809, h-index: 48)
Archeological Papers of The American Anthropological Association     Hybrid Journal   (Followers: 15, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 25, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 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: 231, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 51, 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: 14)
Asia & the Pacific Policy Studies     Open Access   (Followers: 15)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 313, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (Followers: 1, SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 8, SJR: 0.345, h-index: 20)
Asia-pacific J. of Clinical Oncology     Hybrid Journal   (Followers: 6, SJR: 0.554, h-index: 14)
Asia-Pacific J. of Financial Studies     Hybrid Journal   (SJR: 0.241, h-index: 7)
Asia-Pacific Psychiatry     Hybrid Journal   (Followers: 4, SJR: 0.377, h-index: 7)
Asian Economic J.     Hybrid Journal   (Followers: 8, SJR: 0.234, h-index: 21)
Asian Economic Policy Review     Hybrid Journal   (Followers: 4, SJR: 0.196, h-index: 12)
Asian J. of Control     Hybrid Journal   (SJR: 0.862, h-index: 34)
Asian J. of Endoscopic Surgery     Hybrid Journal   (SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 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: 12, SJR: 0.207, h-index: 7)
Asian Social Work and Policy Review     Hybrid Journal   (Followers: 5, SJR: 0.318, h-index: 5)
Asian-pacific Economic Literature     Hybrid Journal   (Followers: 5, SJR: 0.168, h-index: 15)
Assessment Update     Hybrid Journal   (Followers: 4)
Astronomische Nachrichten     Hybrid Journal   (Followers: 2, SJR: 0.701, h-index: 40)
Atmospheric Science Letters     Open Access   (Followers: 29, SJR: 1.332, h-index: 27)
Austral Ecology     Hybrid Journal   (Followers: 13, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 9, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 8, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 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: 4, 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: 44, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 11, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 7, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 4, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 27, SJR: 0.23, h-index: 9)
Australian Economic Review     Hybrid Journal   (Followers: 6, SJR: 0.357, h-index: 21)
Australian Endodontic J.     Hybrid Journal   (Followers: 3, SJR: 0.513, h-index: 24)
Australian J. of Agricultural and Resource Economics     Hybrid Journal   (Followers: 3, SJR: 0.765, h-index: 36)
Australian J. of Grape and Wine Research     Hybrid Journal   (Followers: 5, SJR: 0.879, h-index: 56)
Australian J. of Politics & History     Hybrid Journal   (Followers: 14, SJR: 0.203, h-index: 14)
Australian J. of Psychology     Hybrid Journal   (Followers: 18, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 401, 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: 69, 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: 10, SJR: 0.539, h-index: 70)
Basic and Applied Pathology     Open Access   (Followers: 2, SJR: 0.113, h-index: 4)
Basin Research     Hybrid Journal   (Followers: 5, SJR: 1.54, h-index: 60)
Bauphysik     Hybrid Journal   (Followers: 2, SJR: 0.194, h-index: 5)
Bauregelliste A, Bauregelliste B Und Liste C     Hybrid Journal  
Bautechnik     Hybrid Journal   (Followers: 1, SJR: 0.321, h-index: 11)
Behavioral Interventions     Hybrid Journal   (Followers: 9, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 24, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 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: 16, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 3, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 42, 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: 36, 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: 177, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 14, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 19, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 9, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 37, 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)
BJOG : An Intl. J. of Obstetrics and Gynaecology     Partially Free   (Followers: 225, SJR: 2.083, h-index: 125)

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Journal Cover Addiction Biology
  [SJR: 2.091]   [H-I: 57]   [13 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  [1577 journals]
  • α6 subunit-containing nicotinic receptors mediate low-dose ethanol
           effects on ventral tegmental area neurons and ethanol reward
    • Authors: Scott C. Steffensen; Samuel I. Shin, Ashley C. Nelson, Stephanie S. Pistorius, Stephanie B. Williams, Taylor J. Woodward, Hyun Jung Park, Lindsey Friend, Ming Gao, Fenfei Gao, Devin H. Taylor, M. Foster Olive, Jeffrey G. Edwards, Sterling N. Sudweeks, Lori M. Buhlman, J. Michael McIntosh, Jie Wu
      Abstract: Dopamine (DA) neuron excitability is regulated by inhibitory GABAergic synaptic transmission and modulated by nicotinic acetylcholine receptors (nAChRs). The aim of this study was to evaluate the role of α6 subunit-containing nAChRs (α6*-nAChRs) in acute ethanol effects on ventral tegmental area (VTA) GABA and DA neurons. α6*-nAChRs were visualized on GABA terminals on VTA GABA neurons, and α6*-nAChR transcripts were expressed in most DA neurons, but only a minority of VTA GABA neurons from GAD67 GFP mice. Low concentrations of ethanol (1–10 mM) enhanced GABAA receptor (GABAAR)-mediated spontaneous and evoked inhibition with blockade by selective α6*-nAChR antagonist α-conotoxins (α-Ctxs) and lowered sensitivity in α6 knock-out (KO) mice. Ethanol suppression of VTA GABA neuron firing rate in wild-type mice in vivo was significantly reduced in α6 KO mice. Ethanol (5–100 mM) had no effect on optically evoked GABAAR-mediated inhibition of DA neurons, and ethanol enhancement of VTA DA neuron firing rate at high concentrations was not affected by α-Ctxs. Ethanol conditioned place preference was reduced in α6 KO mice compared with wild-type controls. Taken together, these studies indicate that relatively low concentrations of ethanol act through α6*-nAChRs on GABA terminals to enhance GABA release onto VTA GABA neurons, in turn to reduce GABA neuron firing, which may lead to VTA DA neuron disinhibition, suggesting a possible mechanism of action of alcohol and nicotine co-abuse.GABA (GAD67 GFP: green) terminals (VGAT: blue) on VTA GABA neurons co-express α6*nAChRs (α-Ctx MII: red). Single-cell, quantitative real-time PCR revealed that a subpopulation of GABA neurons in the VTA express α6*nAChRs. Our findings indicate that low concentrations of ethanol act through α6*-nAChRs on GABA terminals to enhance GABA release onto VTA GABA neurons, in turn to reduce GABA neuron firing, which may lead to VTA DA neuron disinhibition, suggesting a possible mechanism of action of alcohol and nicotine co-abuse.
      PubDate: 2017-09-13T02:20:48.169204-05:
      DOI: 10.1111/adb.12559
  • Abnormal gray matter volume and impulsivity in young adults with Internet
           gaming disorder
    • Authors: Deokjong Lee; Kee Namkoong, Junghan Lee, Young-Chul Jung
      Abstract: Reduced executive control is one of the central components of model on the development and maintenance of Internet gaming disorder (IGD). Among the various executive control problems, high impulsivity has consistently been associated with IGD. We performed voxel-based morphometric analysis with diffeomorphic anatomical registration by using an exponentiated Lie algebra algorithm (DARTEL) to investigate the relationship of gray matter abnormalities to impulsivity in IGD. Thirty-one young male adults whose excessive Internet gaming began in early adolescence, and 30 age-matched male healthy controls were examined. IGD subjects showed smaller gray matter volume (GMV) in brain regions implicated in executive control, such as the anterior cingulate cortex and the supplementary motor area. The GMVs in the anterior cingulate cortex and the supplementary motor area were negatively correlated with self-reporting scales of impulsiveness. IGD subjects also exhibited smaller GMV in lateral prefrontal and parietal cortices comprising the left ventrolateral prefrontal cortex and the left inferior parietal lobule when compared with healthy controls. The GMVs in the left ventrolateral prefrontal cortex were negatively correlated with lifetime usage of Internet gaming. These findings suggest that gray matter abnormalities in areas related to executive control may contribute to high impulsivity of young adults with IGD. Furthermore, alterations in the prefrontal cortex were related with long-term excessive Internet gaming during adolescence.Young males with Internet gaming disorder showed smaller gray matter volume in executive control-related brain regions including the anterior cingulate cortex and the ventrolateral prefrontal cortex. Lower gray matter volume in the anterior cingulate cortex correlated with higher impulsivity. Lower gray matter volume in the ventrolateral prefrontal cortex correlated with longer lifetime usage of Internet gaming.
      PubDate: 2017-09-08T06:25:33.422908-05:
      DOI: 10.1111/adb.12552
  • Phosphorylated SNAP25 in the CA1 regulates morphine-associated contextual
           memory retrieval via increasing GluN2B-NMDAR surface localization
    • Authors: Xinjuan Wang; Yan Liu, Meng Jia, Xiaowei Sun, Na Wang, Yijing Li, Cailian Cui
      Abstract: Although our previous studies have demonstrated both protein kinase C (PKC) and GluN2B-containing N-methyl-d-aspartate receptor (GluN2B-NMDAR) play crucial roles in morphine-associated learning and memory, the relationship between them remains unexplored. In this study, we validated the enhanced PKC and membrane GluN2B protein expression in the hippocampal CA1 after morphine conditioned place preference (CPP) expression in rats. Interestingly, we also found that phosphorylation of SNAP25 at Ser187 (pSer187-SNAP25), a PKC-activated target, was significantly increased following morphine CPP expression. Blocking the pSer187-SNAP25 by intra-CA1 injection of an interfering peptide impaired morphine CPP expression and accompanied by the reduced ratio of GluN2B membrane/total in the CA1. In addition, intra-CA1 blockade of pSer187-SNAP25 did not affect natural learning and memory process as evidenced by intact sucrose-induced CPP expression and normal locomotor activity in rats. Therefore, our results reveal that enhanced pSer187-SNAP25 by PKC recruits GluN2B-NMDAR to the membrane surface in the hippocampal CA1 and mediates context-induced addiction memory retrieval. Our findings in this study fill in the missing link and provide better understanding of the molecular mechanisms involved in morphine-associated contextual memory retrieval.Protein kinase C (PKC), pSer187-SNAP25 and GluN2B was critical to morphine conditioned place preference (CPP) expression in the CA1.TAT-S187 peptide in the CA1 impaired morphine CPP expression and decreased the GluN2B surface localization.PKC interacted with pS187-SNAP25 accompanied by increasing GluN2B surface localization in the CA1 after morphine CPP expression.
      PubDate: 2017-09-08T06:16:07.623565-05:
      DOI: 10.1111/adb.12558
  • Cerebral dopaminergic and glutamatergic transmission relate to different
           subjective responses of acute alcohol intake: an in vivo multimodal
           imaging study
    • Authors: Gil Leurquin-Sterk; Jenny Ceccarini, Cleo Lina Crunelle, Akila Weerasekera, Bart Laat, Uwe Himmelreich, Guy Bormans, Koen Van Laere
      Abstract: Converging preclinical evidence links extrastriatal dopamine release and glutamatergic transmission via the metabotropic glutamate receptor 5 (mGluR5) to the rewarding properties of alcohol. To date, human evidence is lacking on how and where in the brain these processes occur. Mesocorticolimbic dopamine release upon intravenous alcohol administration and mGluR5 availability were measured in 11 moderate social drinkers by single-session [18F]fallypride and [18F]FPEB positron emission tomography, respectively. Additionally, baseline and postalcohol glutamate and glutamine levels in the anterior cingulate cortex (ACC) were measured by using proton-magnetic resonance spectroscopy. To investigate differences in reward domains linked to both neurotransmitters, regional imaging data were related to subjective alcohol responses. Alcohol induced significant [18F]fallypride displacement in the prefrontal cortex (PFC), temporal and parietal cortices and thalamus (P 
      PubDate: 2017-09-08T06:06:55.946909-05:
      DOI: 10.1111/adb.12542
  • Self-efficacy modulates the neural correlates of craving in male smokers
           and ex-smokers: an fMRI study
    • Authors: Miki Ono; Takanori Kochiyama, Junya Fujino, Takashi Sozu, Ryosaku Kawada, Naoto Yokoyama, Genichi Sugihara, Toshiya Murai, Hidehiko Takahashi
      Abstract: The regulation of cue-induced craving for cigarettes is a key factor in smoking cessation. Outcomes of smoking cessation have been linked to self-efficacy, faith in one's own ability, in smokers. However, no study has examined the neural basis of self-efficacy during the control of craving. We examined whether self-efficacy can affect the neural response to smoking cues in smokers and ex-smokers using functional magnetic resonance imaging. During scanning, participants were instructed (1) to view smoking-related images passively, (2) to view the smoking-related images with a strategy focused on self-efficacy to control cue-induced craving or (3) to view neutral images. In smokers, the self-efficacy strategy significantly reduced self-reported craving. This strategy was related to increased activation in the rostral medial prefrontal cortex (rmPFC) and the pregenual anterior cingulate cortex in smokers compared with ex-smokers. Furthermore, smokers showed increased effective connectivity between rmPFC and hippocampus and between pregenual anterior cingulate cortex and parahippocampus gyrus when employing the self-efficacy strategy compared with ex-smokers. The magnitude of the rmPFC–hippocampus connectivity was positively correlated with self-reported self-efficacy. Our findings suggest that in smokers, self-efficacy is related to activation and connectivity in brain regions involved in regulating craving and self-assessment. The current study provides evidence for understanding the vunderlying cognitive and neurobiological mechanisms involved in the control of craving to smoke cigarettes.We examined whether self-efficacy can affect the neural response to smoking cues in smokers and ex-smokers using functional magnetic resonance imaging. In smokers, the self-efficacy strategy was related to increased activation in the rostral medial prefrontal cortex (rmPFC) and the pregenual anterior cingulate cortex (pgACC) and increased connectivity between rmPFC and hippocampus and between pgACC and parahippocampus gyrus. Our findings suggest that in smokers, self-efficacy is related to activation and connectivity in brain regions involved in regulating craving and self-assessment.
      PubDate: 2017-09-07T03:20:35.76393-05:0
      DOI: 10.1111/adb.12555
  • Neurotensin in the posterior thalamic paraventricular nucleus: inhibitor
           of pharmacologically relevant ethanol drinking
    • Authors: Surya Pandey; Preeti S. Badve, Genevieve R. Curtis, Sarah F. Leibowitz, Jessica R. Barson
      Abstract: Individuals prone to ethanol overconsumption may have preexisting neurochemical disturbances that contribute to their vulnerability. This study examined the paraventricular nucleus of the thalamus (PVT), a limbic structure recently shown to participate in ethanol intake. To identify individuals prone to ethanol overconsumption, we tested Long–Evans rats in behavioral paradigms and found high levels of vertical time (rearing behavior) in a novel activity chamber to be a consistent predictor of subsequent excessive 20 percent ethanol drinking under the intermittent access model. Examining neurochemicals in the PVT, we found before ethanol exposure that prone rats with high rearing, compared with non-prone rats, had significantly lower levels of neurotensin (NTS) mRNA and peptide in the posterior (pPVT) but not anterior (aPVT) subregion of the PVT. Our additional finding that ethanol intake has no significant impact on either rearing or NTS levels indicates that these measures, which are different in prone rats before ethanol consumption, remain stable after ethanol consumption. The possibility that NTS directly controls ethanol drinking is supported by our finding that NTS administration specifically suppresses ethanol drinking when injected into the pPVT but not aPVT, with this effect occurring exclusively in higher drinkers that presumably have lower endogenous levels of NTS. Further, an NTS antagonist in the pPVT augments intake in lower drinkers with presumably more endogenous NTS, while NTS in the pPVT inhibits novelty-induced rearing that predicts excessive drinking. Together, these results provide strong evidence that low endogenous levels of NTS in the pPVT contribute to an increased propensity toward excessive ethanol drinking.Rats prone to excessive ethanol drinking under the intermittent-access model show high levels of vertical time (rearing) in a novel activity chamber. In the posterior paraventricular nucleus of the thalamus (pPVT), rats identified through this behavior as prone to ethanol drinking show lower levels of the neuropeptide, neurotensin. Injection of neurotensin into the pPVT suppresses ethanol drinking while an antagonist increases it, pointing to this neuropeptide as a novel target for pharmacotherapeutic interventions for alcohol use disorder.
      PubDate: 2017-09-06T11:56:01.888492-05:
      DOI: 10.1111/adb.12546
  • Neural correlates of tobacco cue reactivity predict duration to lapse and
           continuous abstinence in smoking cessation treatment
    • Authors: Max M. Owens; James MacKillop, Joshua C. Gray, Steven R.H. Beach, Michael D. Stein, Raymond S. Niaura, Lawrence H. Sweet
      Abstract: It has been hypothesized that neural reactivity to drug cues in certain limbic/paralimbic regions of the brain is an indicator of addiction severity and a marker for likelihood of success in treatment. To address this question, in the current study, 32 participants (44 percent female) completed a functional magnetic resonance imaging cigarette cue exposure paradigm 2 hours after smoking, and then enrolled in a 9-week smoking cessation treatment program. Neural activation to smoking cues was measured in five a priori defined limbic/paralimbic regions previously implicated with cue reactivity across substances. These included regions of the ventral striatum, anterior cingulate cortex and amygdala. Cox proportional hazard modeling was conducted to predict the number of days to first smoking lapse by using neural activation in these regions. Greater neural activation during pre-treatment exposure to smoking cues in the right ventral striatum, the left amygdala, and the anterior cingulate was associated with longer periods of abstinence following cessation. A similar pattern was present for continuous abstinence for the full duration of treatment. While baseline levels of nicotine dependence were strongly associated with treatment outcome, activation in the right ventral striatum predicted duration of abstinence beyond level of nicotine dependence. These results suggest that pre-treatment reactivity to smoking cues in areas associated with cue reactivity may be associated with successfully maintaining abstinence during treatment. This is consistent with models that propose that as addiction becomes more severe, motivational processing shifts from regions that subserve reward salience and learning to regions responsible motor behavior and habit learning.Reactivity to cues associated with smoking is an established feature of tobacco use disorder. This human fMRI study predicts lapse and continuous abstinence in smoking cessation treatment using brain response to visual cigarette cues in the ventral striatum, amygdala and anterior cingulate cortex. Contrary to prior research, greater activation to smoking cues in these regions was associated with a longer duration of abstinence after quitting and greater likelihood of maintaining abstinence throughout treatment.
      PubDate: 2017-09-06T11:55:04.996452-05:
      DOI: 10.1111/adb.12549
  • Cafeteria diet induces neuroplastic modifications in the nucleus accumbens
           mediated by microglia activation
    • Authors: Miriam Gutiérrez-Martos; Benoit Girard, Sueli Mendonça-Netto, Julie Perroy, Emmanuel Valjent, Rafael Maldonado, Miquel Martin
      Abstract: High-palatable and caloric foods are widely overconsumed due to hedonic mechanisms that prevail over caloric necessities leading to overeating and overweight. The nucleus accumbens (NAc) is a key brain area modulating the reinforcing effects of palatable foods and is crucially involved in the development of eating disorders. We describe that prolonged exposure to high-caloric chocolate cafeteria diet leads to overeating and overweight in mice. NAc functionality was altered in these mice, presenting structural plasticity modifications in medium spiny neurons, increased expression of neuroinflammatory factors and activated microglia, and abnormal responses after amphetamine-induced hyperlocomotion. Chronic inactivation of microglia normalized these neurobiological and behavioural alterations exclusively in mice exposed to cafeteria diet. Our data suggest that prolonged exposure to cafeteria diet produces neuroplastic and functional changes in the NAc that can modify feeding behaviour. Microglia activation and neuroinflammation play an important role in the development of these neurobiological alterations.Frequency-specific power spectra maps were shown for healthy controls and alcoholics. Alcoholics exhibited aberrant frequency oscillation power across the whole frequency bandwidth. These frequency power aberrations were associated with cognitive functioning and may serve as a biomarker for identifying neural targets for repair.
      PubDate: 2017-09-05T02:30:57.604793-05:
      DOI: 10.1111/adb.12541
  • Neural mechanisms of extinguishing drug and pleasant cue associations in
           human addiction: role of the VMPFC
    • Authors: Anna B. Konova; Muhammad A. Parvaz, Vladimir Bernstein, Anna Zilverstand, Scott J. Moeller, Mauricio R. Delgado, Nelly Alia-Klein, Rita Z. Goldstein
      Abstract: The neurobiological mechanisms that underlie the resistance of drug cue associations to extinction in addiction remain unknown. Fear extinction critically depends on the ventromedial prefrontal cortex (VMPFC). Here, we tested if this same region plays a role in extinction of non-fear, drug and pleasant cue associations. Eighteen chronic cocaine users and 15 matched controls completed three functional MRI scans. Participants first learned to associate an abstract cue (the conditioned stimulus, CS) with a drug-related (CSD+) or pleasant (CSP+) image. Extinction immediately followed where each CS was repeatedly presented without the corresponding image. Participants underwent a second identical session 24 hours later to assess retention of extinction learning. Results showed that like fear extinction, non-fear-based extinction relies on the VMPFC. However, extinction-related changes in the VMPFC differed by cue valence and diagnosis. In controls, VMPFC activation to the CSD+ (which was unpleasant for participants) gradually increased as in fear extinction, while it decreased to the CSP+, consistent with a more general role of the VMPFC in flexible value updating. Supporting a specific role in extinction retention, we further observed a cross-day association between VMPFC activation and skin conductance, a classic index of conditioned responses. Finally, cocaine users showed VMPFC abnormalities for both CSs, which, in the case of the CSD+, correlated with craving. These data suggest a global deficit in extinction learning in this group that may hinder extinction-based treatment efforts. More broadly, these data show that the VMPFC, when functionally intact, supports extinction learning in diverse contexts in humans.In this 2-day fMRI study we find that, like fear extinction, non-fear based extinction relies on the ventromedial prefrontal cortex (VMPFC). However, we additionally find that extinction-related changes in the VMPFC differ by (1) what is being extinguished (drug-related versus pleasant cues) and (2) drug addiction diagnosis. While healthy individuals show progressive, cue-specific changes in VMPFC activation, chronic cocaine users do not, suggesting a global extinction-learning deficit in this group that may hinder extinction-based treatment efforts..
      PubDate: 2017-09-05T02:01:16.657524-05:
      DOI: 10.1111/adb.12545
  • Working memory and salivary brain-derived neurotrophic factor as
           developmental predictors of cocaine seeking in male and female rats
    • Authors: Chloe J. Jordan; Susan L. Andersen
      Abstract: Poor working memory is linked to future risk-taking behaviors. Lifelong risk of habitual drug use is highest in individuals who initiate use in early adolescence. We sought to determine in rats whether juvenile traits, specifically poor working memory and low salivary brain-derived neurotrophic factor (BDNF), are related to elevated cocaine taking and relapse in adolescence and adulthood. On postnatal day (P) 20, working memory was assessed using the novel object recognition task in male and female rats. Saliva was assayed at P20 for BDNF before cocaine self-administration on P28 [0.75 or 0.25 mg/kg/infusion for 30 days under a fixed-ratio (FR) 1 to FR5 schedule] and on P94 before relapse after 30-day abstinence in adulthood. A separate cohort of P28 male rats was assayed for object discrimination and BDNF in saliva and the medial prefrontal cortex and dorsolateral striatum. Novel object discrimination correlated positively with salivary BDNF on P20 and dorsolateral striatum levels, but negatively with medial prefrontal cortex BDNF in male rats. In female rats, P20 salivary BDNF negatively correlated with object discrimination. Salivary BDNF positively correlated across age in male rats. Male rats earned more cocaine (0.75 mg/kg) at FR5 and responded more at relapse than did female rats. These elevated relapse rates in male rats were significantly associated with P20 object discrimination and salivary BDNF. Relapse after 0.75 and 0.25 mg/kg in female rats correlated only with object discrimination. In conclusion, poor working memory and low salivary BDNF in juvenile male rats may represent biomarkers for later cocaine use. Further research is needed to identify biomarkers for risk in male rats.Lifelong risk for drug abuse is highest in individuals who initiate use in adolescence. Early identification of drug use risk is therefore critical. We find that in male rats, poor juvenile working memory and low salivary brain-derived neurotrophic factor (BDNF) are associated with elevated cocaine seeking in adolescence and adulthood. In female rats, only working memory is associated with later cocaine seeking. These findings suggest working memory and salivary BDNF may represent biomarkers for later cocaine abuse, although further research is needed in female rats.
      PubDate: 2017-08-31T05:30:54.816034-05:
      DOI: 10.1111/adb.12535
  • Young alcohol binge drinkers have elevated blood endotoxin, peripheral
           inflammation and low cortisol levels: neuropsychological correlations in
    • Authors: Laura Orio; María Antón, Inmaculada Concepción Rodríguez-Rojo, Ángeles Correas, Borja García-Bueno, Monserrat Corral, Fernando Rodríguez Fonseca, Luis Miguel García-Moreno, Fernando Maestú, Fernando Cadaveira
      Abstract: Alcohol binge drinking is a pattern of heavy alcohol consumption that is increasingly practiced by adolescents and young adults. Evidence indicates that alcohol binges induce peripheral inflammation and an exacerbated neuroimmune response that may participate in alcohol-induced cognitive/behavioral dysfunctions. Here, we recruited 20-year-old male and female university students who were identified as binge drinkers for at least 2 years. Compared with controls, young alcohol binge drinkers had elevated levels of blood endotoxin and upregulated markers of the toll-like receptor 4/NF-κB inflammatory pathway in peripheral blood mononuclear cells, together with pro-inflammatory cytokine/chemokine release, oxidative stress and lipid peroxidation. These changes positively correlate with the estimated blood alcohol levels achieved during alcohol binge intoxication and negatively correlate with the time elapsed from the last alcohol consumption. The immune/inflammatory changes were more prominent in female drinkers, who showed elevated levels of alcohol danger-associated molecules, such as high mobility group box 1, indicating that there are sex-related differences in the peripheral inflammatory response to alcohol. In contrast, cortisol levels were decreased in alcohol binge drinkers. Finally, higher levels of inflammatory markers, mainly monocyte chemoattractant protein-1, as well as LPS, high mobility group box 1, toll-like receptor 4, IL-6 and ciclooxygenase-2, correlated with worse scores on episodic memory and executive functioning tasks in female binge drinkers but not in male binge drinkers. These results emphasize possible risky consequences of alcohol use in binge episodes during young adulthood and call attention to sex-related differences in the alcohol-induced immune/inflammatory and neurocognitive responses.Young alcohol binge drinkers have elevated plasma endotoxin levels, immune over-activation, peripheral inflammation and decreased cortisol levels compared with controls. The TLR-4 mediated inflammatory response appears to be higher in female drinkers, who show danger products, such as HMGB1, in blood. Additionally, higher inflammation correlates with worse episodic memory and executive functioning in female but not male drinkers. Results emphasize the risky consequences of alcohol use in binge episodes and call attention to sex-related differences in the alcohol-induced inflammatory response.
      PubDate: 2017-08-25T06:55:41.803948-05:
      DOI: 10.1111/adb.12543
  • Chronic ethanol consumption: role of TLR3/TRIF-dependent signaling
    • Authors: Gizelle M. McCarthy; Anna S. Warden, Courtney R. Bridges, Yuri A. Blednov, R. Adron Harris
      Abstract: Chronic ethanol consumption stimulates neuroimmune signaling in the brain, and Toll-like receptor (TLR) activation plays a key role in ethanol-induced inflammation. However, it is unknown which of the TLR signaling pathways, the myeloid differentiation primary response gene 88 (MyD88) dependent or the TIR-domain-containing adapter-inducing interferon-β (TRIF) dependent, is activated in response to chronic ethanol. We used voluntary (every-other-day) chronic ethanol consumption in adult C57BL/6J mice and measured expression of TLRs and their signaling molecules immediately following consumption and 24 hours after removing alcohol. We focused on the prefrontal cortex where neuroimmune changes are the most robust and also investigated the nucleus accumbens and amygdala. Tlr mRNA and components of the TRIF-dependent pathway (mRNA and protein) were increased in the prefrontal cortex 24 hours after ethanol and Cxcl10 expression increased 0 hour after ethanol. Expression of Tlr3 and TRIF-related components increased in the nucleus accumbens, but slightly decreased in the amygdala. In addition, we demonstrate that the IKKε/TBK1 inhibitor Amlexanox decreases immune activation of TRIF-dependent pathway in the brain and reduces ethanol consumption, suggesting the TRIF-dependent pathway regulates drinking. Our results support the importance of TLR3 and the TRIF-dependent pathway in ethanol-induced neuroimmune signaling and suggest that this pathway could be a target in the treatment of alcohol use disorders.Chronic voluntary alcohol results in time-dependent changes in toll-like receptor pathways in the prefrontal cortex. These changes include increased expression of Tlr3, components of the TRIF-dependent pathway, and the interferon inducible gene Cxcl10. The TRIF-dependent pathway inhibitor Amlexanox reduces Cxcl10 induction in vivo and decreases ethanol consumption, suggesting a role for the TRIF pathway in the regulation of alcohol consumption.
      PubDate: 2017-08-25T06:41:36.335522-05:
      DOI: 10.1111/adb.12539
  • Acute calming effects of alcohol are associated with disruption of the
           salience network
    • Authors: Stephanie M. Gorka; K. Luan Phan, Emma Childs
      Abstract: The mood-altering properties of alcohol are a key motivation for drinking, and people commonly report that they drink alcohol to alleviate stress or to relax. To date, the neural processes associated with the self-reported calming effects of alcohol are not well understood. Existing data imply that alcohol may target and disrupt activity within anterior insula (aINS) and amygdala-based neural networks, which are regions implicated in threat detection and anxious responding. The aims of the current study were (1) to examine the acute effect of alcohol upon functional connectivity within aINS and amygdala circuits and (2) to assess relationships between alcohol effects on functional connectivity and self-reported subjective mood. Healthy men and women (N = 39) who reported regular binge drinking completed a within-subjects, double-blind, placebo-controlled pharmacological functional magnetic resonance imaging experiment with i.v. infusions of either alcohol or placebo. Infusion profiles were personalized for each participant and raised breath alcohol concentration to 80 mg percent. Before, during and after infusions, participants rated their subjective mood (stimulation, sedation and calm). Results showed that alcohol dampened functional connectivity between bilateral aINS seed-regions-of-interest and the dorsal anterior cingulate cortex (dACC), key nodes of the salience network. Additionally, the more that alcohol reduced right aINS-dACC functional connectivity, the calmer participants felt during alcohol administration. Alcohol had no effect on amygdala functional connectivity. These findings suggest that alcohol disrupts aINS-dACC functional connectivity, which may impair detection and appraisal of emotionally salient information and relate to acute relaxing effects of the drug.It is thought that alcohol may produce anxiolytic effects by downregulating limbic activity and disrupting functional connections between frontolimbic circuits that mediate salience processing. Here we show that alcohol infusions dampened functional connectivity between bilateral anterior insula and the dorsal anterior cingulate cortex, key nodes of the salience network, among hazardous drinkers. Furthermore, the more that alcohol reduced right anterior insula-dorsal anterior cingulate cortex connectivity, the calmer participants felt during alcohol administration. Our findings suggest that alcohol disrupts salience determination, which may contribute to feelings of relaxation while intoxicated.
      PubDate: 2017-08-09T01:55:25.959195-05:
      DOI: 10.1111/adb.12537
  • Differential stimulus control of drug-seeking: multimodal reinstatement
    • Authors: Seth R. Batten; Joshua S. Beckmann
      Abstract: In animal models of substance-use disorder, individuals that repeatedly self-administer drugs of abuse have long-lasting neuronal adaptations that do not occur ostensibly in control animals only exposed to natural reinforcers (e.g. food). Because any treatment for substance-use disorder will be given to individuals with drug-taking histories, adequate dissociation of the specific neurobehavioral mechanisms underlying drug reinforcement, natural reinforcement and their associated cue effects requires an experimental model that exposes individuals to both reinforcer conditions, along with their associated stimuli. Furthermore, contingent stimuli that reinforce drug seeking through second-order relationships may produce reinstatement of drug seeking through different neurobehavioral means than non-contingent exposure to stimuli that signal the availability of a drug reinforcer, effectively producing different modes of stimulus-induced reinstatement. Toward experimental isolation of the relationships mentioned, herein, we used a within-session multiple schedule of reinforcement containing both discriminative (SD) and conditioned (CS) stimuli to study stimulus control of drug-taking and food-taking behavior, along with how these functionally distinct cues may differentially reinstate drug-seeking and food-seeking behavior within a single animal. We demonstrate specific stimulus control over drug and food taking; furthermore, we demonstrate that the same stimulus (i.e. cue light) operating as an SD or CS produced differential reinstatement of drug-taking and food-taking behavior. The results suggest that contingent CSs and non-contingent SDs produce reinstatement through different neurobehavioral processes and, within-session multiple schedules, can be used to study different modes of specific stimulus control over drug and food seeking in a single animal with both drug-taking and food-taking history.We used a multiple schedule to demonstrate specific stimulus control over drug and food taking. Furthermore, we demonstrated that the same stimulus operating as a discriminative or conditioned stimulus produced differential reinstatement of drug and food seeking. The results suggest that discriminative and conditioned stimuli produce reinstatement through different neurobehavioral processes, and multiple schedules can be used to study different modes of specific stimulus control over drug and food seeking within individuals.
      PubDate: 2017-08-09T01:50:35.3045-05:00
      DOI: 10.1111/adb.12544
  • Prenatal androgen receptor activation determines adult alcohol and water
           drinking in a sex-specific way
    • Authors: Sabine E. Huber; Iulia Zoicas, Martin Reichel, Christiane Mühle, Christian Büttner, Arif B. Ekici, Volker Eulenburg, Bernd Lenz, Johannes Kornhuber, Christian P. Müller
      Abstract: Alcohol use disorders are major psychiatric disorders. Correlational studies in humans suggested organizational hormonal effects during embryonic development as a risk factor for adult alcohol dependence. Permanent changes can be induced by the activity of sex hormones, like testosterone. Here, we demonstrate a relationship between prenatal androgen receptor (AR)-activation and adult alcohol as well as water drinking in mice in a sex-dependent fashion. Prenatal AR inhibition using the antagonist flutamide decreased adult male alcohol consumption. In contrast, prenatal AR activation by dihydrotestosterone (DHT) led to an increase in adult alcohol consumption in females. These effects were different in adult water drinking, flutamide increased water consumption in females and DHT increased water consumption in males. Prenatal flutamide reduced locomotion and anxiety in adult males but was ineffective in females. We found that prenatal AR activation controls adult levels of monoaminergic modulatory transmitters in the brain and blood hormone levels in a sex-specific way. RNA-Seq analysis confirmed a prenatal AR mediated control of adult expression of alcohol drinking-related genes like Bdnf and Per2. These findings demonstrate that prenatal androgen activity is a risk factor for the establishment of alcohol consumption in adults by its organizational effects.Prenatal sex hormones have organizational effects and have been implicated in alcohol dependence. We found that prenatal manipulation of the hormonal milieu with dihydrotestosterone leads to a highly increased alcohol consumption in female mice, while it has no effect in male mice. We further demonstrate that androgen-receptor activation controls adult levels of monoamines and influences behavior in a sex-specific way.
      PubDate: 2017-08-04T05:15:53.005503-05:
      DOI: 10.1111/adb.12540
  • Addiction-related interactions of pregabalin with morphine in mice and
           humans: reinforcing and inhibiting effects
    • Authors: Elena Vashchinkina; Ossi Piippo, Olga Vekovischeva, Evgeny Krupitsky, Ruslan Ilyuk, Nikholay Neznanov, Kirill Kazankov, Igor Zaplatkin, Esa R. Korpi
      Abstract: The gabapentinoid pregabalin is a rapid-acting anxiolytic and analgesic, possibly suitable in supervised opioid detoxification. However, clinicians have been cautious in using it because of its unknown addictive risk and rising number of mortalities after pregabalin self-medication in opioid abusers. Here, we studied interactions of pregabalin and morphine on reward functions of the dopamine system in mice and the efficacy of pregabalin on withdrawal in opioid addicts. After the treatment of mice with pregabalin and morphine, we used electrophysiology to study neuroplasticity in midbrain slices, self-administration and conditioned place preference tests to investigate the rewarding potential of pregabalin and naloxone-precipitated morphine withdrawal to evaluate opioid withdrawal symptoms. Further, we ran a pilot single-blind, randomized, controlled trial (34 heroin addicts) to evaluate the efficacy and safety of pregabalin in the treatment of opioid withdrawal syndrome. Pregabalin alone did not induce glutamate receptor neuroplasticity of dopamine neurons in the ventral tegmental area, but pre-treatment with pregabalin suppressed morphine-induced neuroplasticity, hyperlocomotion and morphine self-administration. Pregabalin administration after chronic morphine exposure failed to induce any rewarding effects. Instead, pregabalin suppressed withdrawal symptoms in both morphine-treated mice and opioid addicts and was well tolerated. Intriguingly, pregabalin administration after a low dose of morphine strongly facilitated ventral tegmental area neuroplasticity and led to increased conditioned place preference. Pregabalin appears to have the efficacy to counteract both reinforcing and withdrawal effects of opioids, but it also has a potentiating effect when given to mice with existing opioid levels.In this translational study, we investigated the interactions of pregabalin and morphine on reward functions of the dopamine system in mice and the efficacy of pregabalin on withdrawal in opioid addicts. In mice, acute pregabalin suppressed morphine-induced long-term potentiation in the dopamine neurons and withdrawal signs, but pregabalin after morphine administration facilitated this long-term potentiation and rewarding behavior. Chronic experience of morphine in the past did not change the rewarding effects of pregabalin. In humans, pregabalin suppressed withdrawal signs and was well tolerated.
      PubDate: 2017-07-25T02:31:40.796676-05:
      DOI: 10.1111/adb.12538
  • Methamphetamine promotes habitual action and alters the density of
           striatal glutamate receptor and vesicular proteins in dorsal striatum
    • Authors: Teri M. Furlong; Laura H. Corbit, Robert A. Brown, Bernard W. Balleine
      Abstract: Goal-directed actions are controlled by the value of the consequences they produce and so increase when what they produce is valuable and decrease when it is not. With continued invariant practice, however, goal-directed actions can become habits, controlled not by their consequences but by antecedent, reward-related states and stimuli. Here, we show that pre-exposure to methamphetamine (METH) caused abnormally rapid development of habitual control. Furthermore, these drug-induced habits differed strikingly from conventional habits; we found that they were insensitive both to changes in reward value and to the effects of negative feedback. In addition to these behavioral changes, METH exposure produced bidirectional changes to synaptic proteins in the dorsal striatum. In the dorsomedial striatum, a structure critical for goal-directed action, METH exposure was associated with a reduction in glutamate receptor and glutamate vesicular proteins, whereas in the dorsolateral striatum, a region that has previously been implicated in habit learning, there was an increase in these proteins. Together, these results indicate that METH exposure promotes habitual control of action that appears to be the result of bidirectional changes in glutamatergic transmission in the circuits underlying goal-directed and habit-based learning.We demonstrated that exposure to methamphetamine (METH) accelerates habitual control of behavior and alters levels of glutamate-related proteins in dorsal striatum. Using an outcome-devaluation instrumental task, we showed that the actions of METH exposed rats were insensitive to changes in reward value and to negative feedback. METH also produced bidirectional changes in glutamate receptor and glutamate vesicular proteins in dorsomedial and dorsolateral striatum suggesting that METH alters glutamate transmission in circuits underlying goal-directed and habit-based learning.
      PubDate: 2017-07-14T01:10:41.704333-05:
      DOI: 10.1111/adb.12534
  • Neuronal representation of individual heroin choices in the orbitofrontal
    • Authors: Karine Guillem; Viridiana Brenot, Audrey Durand, Serge H. Ahmed
      Abstract: Drug addiction is a harmful preference for drug use over and at the expense of other non-drug-related activities. We previously identified in the rat orbitofrontal cortex (OFC) a mechanism that influences individual preferences between cocaine use and an alternative action rewarded by a non-drug reward (i.e. sweet water). Here, we sought to test the generality of this mechanism to a different addictive drug, heroin. OFC neuronal activity was recorded while rats responded for heroin or the alternative non-drug reward separately or while they chose between the two. First, we found that heroin-rewarded and sweet water-rewarded actions were encoded by two non-overlapping OFC neuronal populations and that the relative size of the heroin population represented individual drug choices. Second, OFC neurons encoding the preferred action—which was the non-drug action in the large majority of individuals—progressively fired more than non-preferred action-coding neurons 1 second after the onset of choice trials and around 1 second before the preferred action was actually chosen, suggesting a pre-choice neuronal competition for action selection. Together with a previous study on cocaine choice, the present study on heroin choice reveals important commonalities in how OFC neurons encode individual drug choices and preferences across different classes of drugs. It also reveals some drug-specific differences in OFC encoding activity. Notably, the proportion of neurons that non-selectively encode both the drug and the non-drug reward was higher when the drug was heroin (present study) than when it was cocaine (previous study). We will discuss the potential functional significance of these commonalities and differences in OFC neuronal activity across different drugs for understanding drug choice.We previously found that the orbitofrontal cortex (OFC) activity influences individual preferences between cocaine use and an alternative non-drug reward. Here, we sought to test the generality of this mechanism to a different addictive drug, heroin. Like with cocaine, OFC neurons encode individual heroin choices. However, there were also some drug-specific differences in OFC encoding suggesting that the OFC would not only encode preference but also resemblance between the drug and non-drug options available for choice.
      PubDate: 2017-07-13T00:42:12.679363-05:
      DOI: 10.1111/adb.12536
  • Aberrant blood-oxygen-level-dependent signal oscillations across frequency
           bands characterize the alcoholic brain
    • Authors: Jui-Yang Hong; Eva M. Müller-Oehring, Adolf Pfefferbaum, Edith V. Sullivan, Dongjin Kwon, Tilman Schulte
      Abstract: Chronic alcoholism is associated with widespread regional differences from controls in brain activity and connectivity dynamics measured by blood-oxygen-level-dependent (BOLD) signals. Identification of alcoholism-related neurofunctional power dynamics using functional magnetic resonance imaging (fMRI) that relate to cognition and behavior may serve as biomarkers of alcoholism. Previously, resting-state fMRI studies examined BOLD signals at a single low-frequency (LF) bandwidth. BOLD signals, however, oscillate systematically at different frequencies and are organized in a resting brain where LF oscillation facilitates long-distance communication between regions across cortical regions, whereas high-frequency (HF) oscillation occurs in closely localized, subcortical areas. Using a frequency power quantification approach, we investigated whether the organization of BOLD signal oscillations across all measured frequency bandwidths is altered in alcoholism and relates to cognitive performance. Frequency-dependent oscillation power differences between 56 sober alcoholics and 56 healthy controls occurred for all frequency bands. Alcoholics exhibited greater frequency oscillation power in the orbitofrontal cortex and less power in the posterior insula within the HF bandwidth than controls. Aberrant orbitofrontal HF power was associated with poorer memory performance and slower psychomotor speed in alcoholics. Middle-frequency and LF power proved sensitive in detecting altered frequency oscillation dynamics in parietal and postcentral cortical regions of alcoholics. This study is novel in identifying alcohol-related differences in BOLD oscillation power of the full fMRI frequency bandwidth. Specifically, HF power aberrations were associated with poorer cognitive functioning in alcoholism and may serve as a biomarker for identifying neural targets for repair.Frequency-specific power spectra maps were shown for healthy controls and alcoholics. Alcoholics exhibited aberrant frequency oscillation power across the whole frequency bandwidth. These frequency power aberrations were associated with cognitive functioning and may serve as a biomarker for identifying neural targets for repair.
      PubDate: 2017-07-12T06:25:32.31255-05:0
      DOI: 10.1111/adb.12532
  • Adolescent alcohol exposure decreases frontostriatal resting-state
           functional connectivity in adulthood
    • Authors: Margaret A. Broadwater; Sung-Ho Lee, Yang Yu, Hongtu Zhu, Fulton T. Crews, Donita L. Robinson, Yen-Yu Ian Shih
      Abstract: Connectivity of the prefrontal cortex (PFC) matures through adolescence, coinciding with emergence of adult executive function and top-down inhibitory control over behavior. Alcohol exposure during this critical period of brain maturation may affect development of PFC and frontolimbic connectivity. Adult rats exposed to adolescent intermittent ethanol (AIE; 5 g/kg ethanol, 25 percent v/v in water, intragastrically, 2-day-on, 2-day-off, postnatal day 25–54) or water control underwent resting-state functional MRI to test the hypothesis that AIE induces persistent changes in frontolimbic functional connectivity under baseline and acute alcohol conditions (2 g/kg ethanol or saline, intraperitoneally administered during scanning). Data were acquired on a Bruker 9.4-T MR scanner with rats under dexmedetomidine sedation in combination with isoflurane. Frontolimbic network regions-of-interest for data analysis included PFC [prelimbic (PrL), infralimbic (IL), and orbitofrontal cortex (OFC) portions], nucleus accumbens (NAc), caudate putamen (CPu), dorsal hippocampus, ventral tegmental area, amygdala, and somatosensory forelimb used as a control region. AIE decreased baseline resting-state connectivity between PFC subregions (PrL-IL and IL-OFC) and between PFC-striatal regions (PrL-NAc, IL-CPu, IL-NAc, OFC-CPu, and OFC-NAc). Acute ethanol induced negative blood-oxygen-level-dependent changes within all regions of interest examined, along with significant increases in functional connectivity in control, but not AIE animals. Together, these data support the hypothesis that binge-like adolescent alcohol exposure causes persistent decreases in baseline frontolimbic (particularly frontostriatal) connectivity and alters sensitivity to acute ethanol-induced increases in functional connectivity in adulthood.Adolescent intermittent ethanol decreased baseline resting-state connectivity between prefrontal cortex subregions (PrL-IL and IL-OFC) and between prefrontal cortex-striatal regions (PrL-NAc, IL-CPu, IL-NAc, OFC-CPu and OFC-NAc). Acute ethanol induced negative BOLD changes within all ROIs examined, along with significant increases in functional connectivity in control, but not adolescent intermittent ethanol animals. Together these data support the hypothesis that binge-like adolescent alcohol exposure causes persistent decreases in frontostriatal connectivity and alters sensitivity to acute ethanol-induced increases in functional connectivity in adulthood.
      PubDate: 2017-07-09T22:40:56.1361-05:00
      DOI: 10.1111/adb.12530
  • Cocaine and HIV are independently associated with neural activation in
           response to gain and loss valuation during economic risky choice
    • Authors: Christina S. Meade; Merideth Addicott, Andrea L. Hobkirk, Sheri L. Towe, Nan-Kuei Chen, Sriramkumar Sridharan, Scott A. Huettel
      Abstract: Stimulant abuse is disproportionately common in HIV-positive persons. Both HIV and stimulants are independently associated with deficits in reward-based decision making, but their interactive and/or additive effects are poorly understood despite their prevalent co-morbidity. Here, we examined the effects of cocaine dependence and HIV infection in 69 adults who underwent functional magnetic resonance imaging while completing an economic loss aversion task. We identified two neural networks that correlated with the evaluation of the favorable characteristics of the gamble (i.e. higher gains/lower losses: ventromedial prefrontal cortex, anterior cingulate, anterior and posterior precuneus and visual cortex) versus unfavorable characteristics of the gamble (i.e. lower gains/higher losses: dorsal prefrontal, lateral orbitofrontal, posterior parietal cortex, anterior insula and dorsal caudate). Behaviorally, cocaine and HIV had additive effects on loss aversion scores, with HIV-positive cocaine users being the least loss averse. Cocaine users had greater activation in brain regions that tracked the favorability of gamble characteristics (i.e. increased activation to gains, but decreased activation to losses). In contrast, HIV infection was independently associated with lesser activation in regions that tracked the unfavorability of gamble characteristics. These results suggest that cocaine is associated with an overactive reward-seeking system, while HIV is associated with an underactive cognitive control system. Together, these alterations may leave HIV-positive cocaine users particularly vulnerable to making unfavorable decisions when outcomes are uncertain.We examined the effects of cocaine dependence and HIV infection in 69 adults who underwent functional magnetic resonance imaging while completing an economic risk task. Cocaine was associated with greater activation in response to increasing favorability of gambles (i.e., higher gains/lower losses) in reward-related regions (e.g., ACC and VMPFC), while HIV was associated with less activation in response to increasing unfavorability of gambles (i.e., lower gains/higher losses) in cognitive control regions (e.g., DLPFC and PPC).
      PubDate: 2017-07-06T05:18:28.364131-05:
      DOI: 10.1111/adb.12529
  • A new generation of mTORC1 inhibitor attenuates alcohol intake and reward
           in mice
    • Authors: Nadege Morisot; Christopher J. Novotny, Kevan M. Shokat, Dorit Ron
      Abstract: Alcohol use disorder (AUD) is a chronic condition associated with devastating socioeconomic consequences. Yet, pharmacotherapies to treat behavioral phenotypes such as uncontrolled heavy drinking are limited. Studies in rodents suggest that the mammalian target of rapamycin complex 1 (mTORC1) plays an important role in mechanisms underlying alcohol drinking behaviors as well as alcohol seeking and relapse. These preclinical evidence suggest that mTORC1 may be a therapeutic target for the treatment of AUD. Thus, the aim of the present study was to test the potential use of newly developed mTORC1 inhibitors, RapaLink-1 and MLN0128, in preclinical mouse models of AUD. First, we used the intermittent access to 20 percent alcohol in a two-bottle choice paradigm and tested the efficacy of the drugs to reduce alcohol intake in mice with a history of binge drinking and withdrawal. We found that both inhibitors reduce excessive alcohol intake and preference with RapaLink-1 exhibiting higher efficacy. We further observed that RapaLink-1 attenuates alcohol consumption during the first alcohol-drinking session in naïve mice, and interestingly, the effect was still present 14 days after the initial treatment with the drug. We also found that RapaLink-1 did not alter the consumption of water or saccharin, revealing a specific effect of the inhibitor on alcohol intake. Finally, we report that RapaLink-1 blocks the retrieval but not acquisition of alcohol place preference without affecting locomotion. Together, our findings suggest that RapaLink-1 may be developed as a new medication to treat and prevent the development of AUD.Mammalian target of rapamycin complex 1 (mTORC1) contributes to mechanisms underlying excessive alcohol consumption. In this manuscript, Morisot et al. examined the efficacy of new classes of mTORC1 inhibitors to attenuate alcohol-dependent behaviors in mice. The authors found that systemic administration of the mTORC1 inhibitor, Rapalink-1, inhibits alcohol intake and reward and produces a long-lasting inhibition when administered prior to the first binge drinking session. Together, the findings suggest that mTORC1 inhibitors may be developed for the treatment of alcohol use disorder.
      PubDate: 2017-07-06T00:00:54.288169-05:
      DOI: 10.1111/adb.12528
  • Context-induced relapse to cocaine seeking after punishment-imposed
           abstinence is associated with activation of cortical and subcortical brain
    • Authors: Yann Pelloux; Jennifer K. Hoots, Carlo Cifani, Sweta Adhikary, Jennifer Martin, Angelica Minier-Toribio, Jennifer M. Bossert, Yavin Shaham
      Abstract: We recently developed a rat model of context-induced relapse to alcohol seeking after punishment-imposed abstinence to mimic relapse after self-imposed abstinence due to adverse consequences of drug use. Here, we determined the model's generality to cocaine and have begun to explore brain mechanisms of context-induced relapse to cocaine seeking after punishment-imposed abstinence, using the activity marker Fos. In exp. 1, we trained rats to self-administer cocaine (0.75 mg/kg/infusion, 6 hours/day, 12 days) in context A. Next, we transferred them to context B where for the paired group, but not unpaired group, 50 percent of cocaine-reinforced lever presses caused aversive footshock. We then tested the rats for cocaine seeking under extinction conditions in contexts A and B. We also retested them for relapse after retraining in context A and repunishment in context B. In exp. 2, we used Fos immunoreactivity to determine relapse-associated neuronal activation in brain regions of rats exposed to context A, context B or neither context. Results showed the selective shock-induced suppression of cocaine self-administration and context-induced relapse after punishment-imposed abstinence in rats exposed to paired, but not unpaired, footshock. Additionally, context-induced relapse was associated with selective activation of dorsal and ventral medial prefrontal cortex, anterior insula, dorsal striatum, basolateral amygdala, paraventricular nucleus of the thalamus, lateral habenula, substantia nigra, ventral subiculum, and dorsal raphe, but not nucleus accumbens, central amygdala, lateral hypothalamus, ventral tegmental area and other brain regions. Together, context-induced relapse after punishment-imposed abstinence generalizes to rats with a history of cocaine self-administration and is associated with selective activation of cortical and subcortical regions.We recently developed a rat model of context-induced relapse to alcohol seeking after punishment-imposed abstinence to mimic relapse after self-imposed abstinence due to adverse consequences of drug use. Here, we determined the model's generality to cocaine and have begun to explore brain mechanisms of context-induced relapse to cocaine seeking after punishment-imposed abstinence, using the activity marker Fos. We showed the context-induced relapse after punishment-imposed abstinence generalizes to rats with a history of cocaine self-administration and is associated with selective activation of cortical and subcortical regions.
      PubDate: 2017-06-29T05:10:41.61999-05:0
      DOI: 10.1111/adb.12527
  • Fatty acid amide hydrolase (FAAH) inactivation confers enhanced
           sensitivity to nicotine-induced dopamine release in the mouse nucleus
    • Authors: Francisco J. Pavon; Antonia Serrano, Nimish Sidhpura, Ilham Polis, David Stouffer, Fernando Rodriguez Fonseca, Benjamin F. Cravatt, Rémi Martin-Fardon, Loren H. Parsons
      Abstract: Nicotine exerts its rewarding effects by promoting an increase in dopamine (DA) release in the nucleus accumbens (NAc), and this process is influenced by the endocannabinoid system. Fatty acid amide hydrolase (FAAH) is the main enzyme responsible for the degradation of the endocannabinoid anandamide and other non-cannabinoid N-acylethanolamines. Previous research has reported that both genetic deletion and pharmacological inhibition of FAAH enhance nicotine-induced conditioned place preference at low doses. We conducted a microdialysis study to characterize nicotine-induced changes in DA and serotonin (5-HT) levels in the NAc of FAAH knockout (KO) mice using a conditioned place preference-like paradigm with three nicotine doses (0.1, 1 and 10 mg/kg, s.c.). Additionally, the effects of the selective FAAH inhibitor PF-3845 (10 mg/kg, i.p.) were also examined. Our data indicated that compared with wild-type mice, genetic deletion of FAAH selectively enhanced the effect of low-dose nicotine on DA release (p 
      PubDate: 2017-06-29T03:55:38.59115-05:0
      DOI: 10.1111/adb.12531
  • CB1 and ethanol effects on glutamatergic transmission in the central
           amygdala of male and female msP and Wistar rats
    • Authors: Dean Kirson; Christopher Shaun Oleata, Loren Howell Parsons, Roberto Ciccocioppo, Marisa Roberto
      Abstract: The central amygdala (CeA) is involved in the processing of anxiety and stress and plays a role in ethanol consumption. Chronic ethanol recruits stress systems in the CeA, leading to aversive withdrawal symptoms. Although primarily GABAergic, CeA contains glutamatergic afferents, and we have reported inhibitory effects of ethanol on locally evoked glutamatergic responses in CeA of Wistar and Marchigian Sardinian alcohol-preferring (msP) rats. Notably, msP rats display enhanced anxiety, stress and alcohol drinking, simulating the alcohol-dependent phenotype. Endocannabinoids are also involved in regulation of stress, and we previously demonstrated that cannabinoid receptor type 1 (CB1) activation decreases CeA GABAergic signaling and blocks ethanol enhancement of GABAergic signaling. Here, we sought to investigate the effects of CB1 activation (WIN 55,212–2; Win) and antagonism (AM251) with and without acute ethanol on glutamatergic synapses in CeA of female and male Wistar and msP rats. Using intracellular sharp pipette electrophysiology, we examined the effects of CB1 compounds on locally evoked excitatory postsynaptic potentials (EPSPs) in CeA and compared effects between strains, gender and estrous cycle. Acute ethanol decreased EPSP amplitudes in Wistars, and in male but not female msPs. Win decreased EPSP amplitudes in msPs, and in male but not female Wistars. Combined application of Win and ethanol resulted in strain-specific effects in female rats. We found no tonic CB1 signaling at glutamatergic synapses in CeA of any groups, and no interaction with ethanol. Collectively, these observations demonstrate sex–strain-specific differences in ethanol and endocannabinoid effects on CeA glutamatergic signaling.The Marchigian Sardinian alcohol-preferring (msP) rat simulates the high-stress alcohol-dependent phenotype. We examined cannabinoid receptor type 1 (CB1)-mediated effects on evoked glutamatergic signaling in the central amygdala (CeA), and interactions with acute ethanol, in male and female msP and Wistar rats. We found strain-dependent/sex-dependent inhibition of excitatory postsynaptic potentials with ethanol and CB1 agonism and strain-specific effects of the combined drugs in female rats. These observations demonstrate sex differences in response to the intersection of stress and alcohol.
      PubDate: 2017-06-28T02:31:49.174303-05:
      DOI: 10.1111/adb.12525
  • Long-term subregion-specific encoding of enhanced ethanol intake by D1DR
           medium spiny neurons of the nucleus accumbens
    • Authors: Rafael Renteria; Tavanna R. Buske, Richard A. Morrisett
      Abstract: The nucleus accumbens (NAc) is a critical component of the mesocorticolimbic system and is involved in mediating the motivational and reinforcing aspects of ethanol consumption. Chronic intermittent ethanol (CIE) exposure is a reliable model to induce ethanol dependence and increase volitional ethanol consumption in mice. Following a CIE-induced escalation of ethanol consumption, NMDAR (N-methyl-D-aspartate receptor)-dependent long-term depression in D1 dopamine receptor expressing medium spiny neurons of the NAc shell was markedly altered with no changes in plasticity in D1 dopamine receptor medium spiny neurons from the NAc core. This disruption of plasticity persisted for up to 2 weeks after cessation of ethanol access. To determine if changes in AMPA receptor (AMPAR) composition contribute to this ethanol-induced neuroadaptation, we monitored the rectification of AMPAR excitatory postsynaptic currents (EPSCs). We observed a marked decrease in the rectification index in the NAc shell, suggesting the presence of GluA2-lacking AMPARs. There was no change in the amplitude of spontaneous EPSCs (sEPSCs), but there was a transient increase in sEPSC frequency in the NAc shell. Using the paired pulse ratio, we detected a similar transient increase in the probability of neurotransmitter release. With no change in sEPSC amplitude, the change in the rectification index suggests that GluA2-containing AMPARs are removed and replaced with GluA2-lacking AMPARs in the NAc shell. This CIE-induced alteration in AMPAR subunit composition may contribute to the loss of NMDAR-dependent long-term depression in the NAc shell and therefore may constitute a critical neuroadaptive response underlying the escalation of ethanol intake in the CIE model.Using a model of alcohol dependence, chronic intermittent ethanol (CIE), we observed a long-term disruption in the expression of NMDAR-dependent plasticity and a change in the rectification index of AMPA receptor mediated currents in D1 medium spiny neurons (MSNs) of the NAc shell but not the NAc core. These changes in plasticity and excitatory signaling in D1 MSNs of the NAc shell may constitute a critical neuroadaptive response underlying the escalation of ethanol intake in the CIE model.
      PubDate: 2017-06-28T01:40:28.187403-05:
      DOI: 10.1111/adb.12526
  • Noradrenergic signaling in the VTA modulates cocaine craving
    • Authors: Wojciech Barnaba Solecki; Klaudia Szklarczyk, Kamil Pradel, Krystyna Kwiatkowska, Grzegorz Dobrzański, Ryszard Przewłocki
      Abstract: Exposure to drug-associated cues evokes drug-seeking behavior and is regarded as a major cause of relapse. Conditional stimulus upregulates noradrenaline (NA) system activity, but the drug-seeking behavior depends particularly on phasic dopamine signaling downstream from the ventral tegmental area (VTA). The VTA dopamine-ergic activity is regulated via the signaling of alpha1-adrenergic and alpha2-adrenergic receptors (α1-ARs and α2-ARs); thus, the impact of the conditional stimulus on drug-seeking behavior might involve NAergic signaling in the VTA. To date, the role of VTA ARs in regulating cocaine seeking was not studied. We found that cocaine seeking under extinction conditions in male Sprague–Dawley rats was attenuated by intra-VTA prazosin or terazosin—two selective α1-AR antagonists. In contrast, cocaine seeking was facilitated by intra-VTA administration of the selective α1-AR agonist phenylephrine as well as α2-AR antagonist RX 821002, whereas the selective β-AR antagonist propranolol had no effects. In addition, blockade of α1-AR in the VTA prevented α2-AR antagonist-induced enhancement of cocaine seeking. Importantly, the potential non-specific effects of the VTA AR blockade on cocaine seeking could be excluded, because none of the AR antagonists influenced sucrose seeking under extinction conditions or locomotor activity in the open field test. These results demonstrate that NAergic signaling potently and selectively regulates cocaine seeking during early cocaine withdrawal via VTA α1-AR and α2-AR but not β-AR. Our findings provide new insight into the NAergic mechanisms that underlie cocaine craving.Cocaine seeking under extinctiong criteria in rats is attenuated by intra-ventral tegmental area (VTA) selective α1-AR antagonists (prazosin and terazois). In contrast, cocaine seeking is facilitated by intra-VTA administration of the selective α1-AR agonist (phenylephrine) as well as α2-AR antagonist (RX 821002), whereas the selective β-AR antagonist (propranolol) has no effects. Importantly, the potential nonspecific effects of the VTA AR blockade on cocaine seeking could be excluded, because none of the AR antagonists influenced sucrose seeking or locomotor activity.
      PubDate: 2017-06-21T03:51:39.323586-05:
      DOI: 10.1111/adb.12514
  • Novel role and regulation of HDAC4 in cocaine-related behaviors
    • Authors: Rachel D. Penrod; Maria B. Carreira, Makoto Taniguchi, Jaswinder Kumar, Stephanie A. Maddox, Christopher W. Cowan
      Abstract: Epigenetic mechanisms have been proposed to contribute to persistent aspects of addiction-related behaviors. One family of epigenetic molecules that may regulate maladaptive behavioral changes produced by cocaine use are the histone deacetylases (HDACs)—key regulators of chromatin and gene expression. In particular, the class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) respond to changes in neuronal activity by modulating their distribution between the nucleus and cytoplasm—a process controlled in large part by changes in phosphorylation of conserved residues. Cocaine triggers a transient nuclear accumulation of HDAC5 that functions to limit the development of cocaine reward behavior. However, the role and regulation of the close family member, HDAC4, in cocaine behaviors remain largely unknown. In this study, we report that cocaine and cAMP signaling in striatum produced differential phosphorylation and subcellular localization of HDAC4 and HDAC5. Unlike HDAC5, cocaine exposure induced a modest hyperphosphorylation and nuclear export of HDAC4. Genetic deletion of HDAC4 in the nucleus accumbens reduced acute cocaine-produced locomotion, maximum locomotor sensitization and cocaine reward-related behavior. Interestingly, overexpression of an HDAC4 cytoplasm-concentrated mutant (S266E) increased cocaine reward behavior in the cocaine conditioned place preference assay, suggesting that cocaine-induced nuclear export of HDAC4 might function to facilitate the development of cocaine reward behaviors through a role in the cell cytoplasm. Together, our findings suggest that, despite high sequence homology, HDAC4 and HDAC5 are oppositely regulated by cocaine-induced signaling in vivo and have distinct roles in regulating cocaine behaviors.In the nucleus accumbens, HDAC4 is hyperphosphorylated and re-localized to the cytoplasm in response to cocaine. Loss of neuronal HDAC4 in the adult mouse nucleus accumbens reduces behavioral responses to cocaine. Overexpression of a phospho-mimetic mutant of HDAC4 enhances cocaine reward behavior, suggesting a possible cytoplasmic role in addiction-related behaviors.
      PubDate: 2017-06-21T03:22:07.306139-05:
      DOI: 10.1111/adb.12522
  • Locomotor sensitization is expressed by ghrelin and D1 dopamine receptor
           agonist in the nucleus accumbens core in amphetamine pre-exposed rat
    • Authors: Ju Kyong Jang; Wha Young Kim, Bo Ram Cho, Jung Won Lee, Jeong-Hoon Kim
      Abstract: Ghrelin modulates mesolimbic dopaminergic pathways in the brain in addition to its role in feeding. We investigated what roles ghrelin in the nucleus accumbens (NAcc) core may play in mediating locomotor activating effects of amphetamine (AMPH). First, when rats were administered with AMPH (1 mg/kg, i.p.) following a bilateral microinjection of ghrelin (0.1 or 0.5 μg/side) into the NAcc core, their locomotor activity was significantly enhanced, while these effects were blocked by co-microinjection of ghrelin receptor antagonist (0.5 μg/side) into this site. Second, we pre-exposed rats to saline or amphetamine (1 mg/kg, i.p.) every 2 to 3 days for a total of four times. After 2 weeks of drug-free withdrawal period, we examined the effect of saline, ghrelin (0.5 μg/side), D1 dopamine receptor agonist, SKF81297 (0.5 μg/side) or ghrelin (0.5 μg/side) + SKF81297 (0.5 μg/side) directly microinjected into the NAcc core on locomotor activity. When we measured rats' locomotor activity for 1 hour immediately following microinjections, only ghrelin + SKF81297 produces sensitized locomotor activity, while all others have no effects. These results suggest that ghrelin may have a distinct role in the NAcc core to provoke the sensitized locomotor activity induced by psychomotor stimulants, and further, it may produce these effects by interaction with D1 dopamine receptors.Ghrelin modulates mesolimbic dopaminergic pathways in the brain in addition to its role in feeding. Here, we showed that ghrelin in the nucleus accumbens core significantly enhanced acute amphetamine-induced locomotor activity. Further, ghrelin when co-microinjected into this site with SKF 81297 produced sensitized locomotor activity in amphetamine pre-exposed rats. These results suggest that ghrelin has a distinct role in the nucleus accumbens core to provoke the sensitized locomotor activity induced by psychomotor stimulants, with the help of D1 dopamine receptors.
      PubDate: 2017-06-21T01:55:28.631528-05:
      DOI: 10.1111/adb.12533
  • Buprenorphine requires concomitant activation of NOP and MOP receptors to
           reduce cocaine consumption
    • Authors: Marsida Kallupi; Qianwei Shen, Giordano Guglielmo, Dennis Yasuda, V. Blair Journigan, Nurulain T. Zaveri, Roberto Ciccocioppo
      Abstract: Buprenorphine's clinical use is approved for the treatment of heroin addiction; however, evidence supporting its efficacy in cocaine abuse also exists. While for heroin it has been demonstrated that the effect of buprenorphine is mediated by its ability to activate μ-opioid peptide receptor (MOP) receptors, the mechanism through which it attenuates cocaine intake remains elusive. We explored this mechanism using operant models where rodents were trained to chronically self-administer cocaine for 2 hours daily. Buprenorphine (0.3, 1.0 and 3.0 mg/kg) given intraperitoneally 90 minutes before access to cocaine significantly and dose dependently reduced its intake. Pre-treatment with naltrexone or with the selective nociceptin/orphanin FQ peptide (NOP) antagonist SB-612111 did not prevent buprenorphine-induced reduction of cocaine intake. However, when naltrexone and SB-612111 were combined, the effect of buprenorphine on cocaine was completely prevented. To confirm that co-activation of MOP and NOP receptors is the underlying mechanism through which buprenorphine reduces cocaine intake, three compounds, namely, AT-034, AT-201 and AT-202, with a range of affinity and intrinsic activity profiles for MOP and NOP receptors, but weak ability for kappa-opioid peptide receptor (KOP) transmission, were tested. Consistent with our hypothesis based on buprenorphine's effects, results demonstrated that AT-034 and AT-201, which co-activate MOP and NOP receptors, reduced cocaine self-administration like buprenorphine. AT-202, which selectively stimulates NOP receptors, was not effective. Together, these data demonstrate that for buprenorphine, co-activation of MOP and NOP receptors is essential to reduce cocaine consumption. These results open new vistas on the treatment of cocaine addiction by developing compounds with mixed MOP/NOP agonist properties.Buprenorphine, at all doses tested, reduced significantly, in a dose-dependent manner, the number of cocaine rewards. However, treatment with the combination (SB-612111 30.0 mg + Nltx 2.5 mg) completely prevented the reduction of cocaine self-administration by buprenorphine.
      PubDate: 2017-06-21T01:14:08.285903-05:
      DOI: 10.1111/adb.12513
  • Regional cerebral blood flow in opiate dependence relates to substance use
           and neuropsychological performance
    • Authors: Donna E. Murray; Timothy C. Durazzo, Thomas P. Schmidt, Troy A. Murray, Christoph Abé, Joseph Guydish, Dieter J. Meyerhoff
      Abstract: Neuroimaging of opiate-dependent individuals indicates both altered brain structure and function. Magnetic resonance-based arterial spin labeling has been used to measure noninvasively cerebral blood flow (i.e. perfusion) in alcohol, tobacco and stimulant dependence; only one arterial spin labeling paper in opiate-dependent individuals demonstrated frontal and parietal perfusion deficits. Additional research on regional brain perfusion in opiate dependence and its relationship to cognition and self-regulation (impulsivity, risk taking and decision making) may inform treatment approaches for opiate-dependent individuals. Continuous arterial spin labeling magnetic resonance imaging at 4 T and neuropsychological measures assessed absolute brain perfusion levels, cognition and self-regulation in 18 cigarette smoking opiate-dependent individuals (sODI) stable on buprenorphine maintenance therapy. The sODI were compared with 20 abstinent smoking alcohol-dependent individuals (a substance-dependent control group), 35 smoking controls and 29 nonsmoking controls. sODI had lower perfusion in several cortical and subcortical regions including regions within the brain reward/executive oversight system compared with smoking alcohol-dependent individuals and nonsmoking controls. Perfusion was increased in anterior cingulate cortex and globus pallidus of sODI. Compared with all other groups, sODI had greater age-related declines in perfusion in most brain reward/executive oversight system and some other regions. In sODI, lower regional perfusion related to greater substance use, higher impulsivity and weaker visuospatial skills. Overall, sODI showed cortical and subcortical hypoperfusion and hyperperfusion. Relating to neuropsychological performance and substance use quantities, the frontal perfusion alterations are clinically relevant and constitute potential targets for pharmacological and cognitive-based therapeutic interventions to improve treatment outcome in opiate dependence.Regional brain perfusion in opiate dependent individuals (sODI) was measured with arterial spin labeling magnetic resonance imaging. Perfusion was increased in anterior cingulate cortex and globus pallidus of sODI. sODI had greater age-related declines in perfusion in most brain reward/executive oversight system regions than control groups (smokers and non-smokers) and a substance-dependent control group. In sODI, lower regional perfusion was related to greater substance use, higher impulsivity, and weaker visuospatial skills. Overall, sODI showed cortical and subcortical hypo-perfusion and hyperperfusion.
      PubDate: 2017-06-19T04:45:53.97421-05:0
      DOI: 10.1111/adb.12523
  • Dentate gyrus neurogenesis ablation via cranial irradiation enhances
           morphine self-administration and locomotor sensitization
    • Authors: Sarah E. Bulin; Matthew L. Mendoza, Devon R. Richardson, Kwang H. Song, Timothy D. Solberg, Sanghee Yun, Amelia J. Eisch
      Abstract: Adult dentate gyrus (DG) neurogenesis is important for hippocampal-dependent learning and memory, but the role of new neurons in addiction-relevant learning and memory is unclear. To test the hypothesis that neurogenesis is involved in the vulnerability to morphine addiction, we ablated adult DG neurogenesis and examined morphine self-administration (MSA) and locomotor sensitization. Male Sprague–Dawley rats underwent hippocampal-focused, image-guided X-ray irradiation (IRR) to eliminate new DG neurons or sham treatment (Sham). Six weeks later, rats underwent either MSA (Sham = 16, IRR = 15) or locomotor sensitization (Sham = 12, IRR = 12). Over 21 days of MSA, IRR rats self-administered ~70 percent more morphine than Sham rats. After 28 days of withdrawal, IRR rats pressed the active lever 40 percent more than Sham during extinction. This was not a general enhancement of learning or locomotion, as IRR and Sham groups had similar operant learning and inactive lever presses. For locomotor sensitization, both IRR and Sham rats sensitized, but IRR rats sensitized faster and to a greater extent. Furthermore, dose–response revealed that IRR rats were more sensitive at a lower dose. Importantly, these increases in locomotor activity were not apparent after acute morphine administration and were not a byproduct of irradiation or post-irradiation recovery time. Therefore, these data, along with other previously published data, indicate that reduced hippocampal neurogenesis confers vulnerability for multiple classes of drugs. Thus, therapeutics to specifically increase or stabilize hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.Rats underwent hippocampal-focused, image-guided X-ray irradiation to eliminate new dentate gyrus neurons or received a control treatment. Irradiated rats self-administered ˜70% more morphine than control rats, and pressed the active lever ˜40% more than control rats during extinction. Irradiated rats also sensitized faster and to a greater extent than control rats in locomotor sensitization.
      PubDate: 2017-06-19T03:55:58.774177-05:
      DOI: 10.1111/adb.12524
  • Temporally specific miRNA expression patterns in the dorsal and ventral
           striatum of addiction-prone rats
    • Authors: Rikki K. Quinn; Morgan H. James, Guy E. Hawkins, Amanda L. Brown, Andrew Heathcote, Doug W. Smith, Murray J. Cairns, Christopher V. Dayas
      Abstract: MicroRNAs (miRNAs) within the ventral and dorsal striatum have been shown to regulate addiction-relevant behaviours. However, it is unclear how cocaine experience alone can alter the expression of addiction-relevant miRNAs within striatal subregions. Further, it is not known whether differential expression of miRNAs in the striatum contributes to individual differences in addiction vulnerability. We first examined the effect of cocaine self-administration on the expression of miR-101b, miR-137, miR-212 and miR-132 in nucleus accumbens core and nucleus accumbens shell (NAcSh), as well as dorsomedial striatum and dorsolateral striatum (DLS). We then examined the expression of these same miRNAs in striatal subregions of animals identified as being ‘addiction-prone’, either immediately following self-administration training or following extinction and relapse testing. Cocaine self-administration was associated with changes in miRNA expression in a regionally discrete manner within the striatum, with the most marked changes occurring in the nucleus accumbens core. When we examined the miRNA profile of addiction-prone rats following self-administration, we observed increased levels of miR-212 in the dorsomedial striatum. After extinction and relapse testing, addiction-prone rats showed significant increases in the expression of miR-101b, miR-137, miR-212 and miR-132 in NAcSh, and miR-137 in the DLS. This study identifies temporally specific changes in miRNA expression consistent with the engagement of distinct striatal subregions across the course of the addiction cycle. Increased dysregulation of miRNA expression in NAcSh and DLS at late stages of the addiction cycle may underlie habitual drug seeking, and may therefore aid in the identification of targets designed to treat addiction.Bayesian model averaging (BMA) is a novel method to identify rats with a predisposition to addiction and relapse vulnerability using early behaviour traits. Using our BMA model, we have shown that addiction-prone rats show a distinct temporal profile in miRNA expression in the striatum compared to addiction-resistant rats. Here we show that key miRNA involved in synaptic plasticity processes, including miR-137, and those previously implicated in addiction behaviours, including miR-212, are dysregulated throughout the addiction cycle.
      PubDate: 2017-06-13T23:30:33.334271-05:
      DOI: 10.1111/adb.12520
  • Effect of N-acetylcysteine on motivation, seeking and relapse to ethanol
    • Authors: Sophie Lebourgeois; María Carmen González-Marín, Jerome Jeanblanc, Mickael Naassila, Catherine Vilpoux
      Abstract: Alcohol use disorder is a chronic and highly relapsing disorder, characterized by a loss of control over alcohol consumption and craving. Several studies suggest a key role of glutamate in this disorder. In recent years, the modulation of cystine/glutamate exchange via the xc− system has emerged as a new therapeutic alternative for reducing the excitatory glutamatergic transmission observed after ethanol self-administration in both rats and humans. The objective of this study was to determine whether a treatment with N-acetylcysteine (NAC), a cystine prodrug, could reduce ethanol self-administration, ethanol-seeking behavior and reacquisition of ethanol self-administration. Male Long Evans rats were trained to self-administer 20 percent ethanol in operant cages for several weeks. Once the consumption surpassed 1 g of ethanol/kg body weight/15 minutes, the effect of an acute intraperitoneal injection of NAC (0, 25, 50 or 100 mg/kg) 1 hour before the beginning of each test was evaluated on different aspects of the operant self-administration behavior. We demonstrated antimotivational properties of NAC (100 mg/kg), as ethanol-reinforced responding was reduced in a fixed ratio (−35 percent) and in a progressive ratio schedule (−81 percent). NAC also reduced ethanol-seeking behavior (−77 percent) evaluated as extinction responding in a single extinction session. NAC was able to reduce reacquisition in rats that were abstinent for 17 days, while NAC had no effect on ethanol relapse in rats previously exposed to six extinction sessions. Overall, our results demonstrate that NAC limits motivation, seeking behavior and reacquisition in rats, making it a potential new treatment for the maintenance of abstinence.We report here N-acetylcysteine (NAC) efficacy to reduce operant ethanol self-administration in rats during short-time session of 15 minutes. NAC also reduces seeking and reacquisition following protracted abstinence. Our results suggest for the first time that NAC is a potential new anticraving treatment for reduction of alcohol relapse.
      PubDate: 2017-05-30T07:16:11.483229-05:
      DOI: 10.1111/adb.12521
  • Effects of sleep on substance use in adolescents: a longitudinal
    • Authors: Tam T. Nguyen-Louie; Ty Brumback, Matthew J. Worley, Ian M. Colrain, Georg E. Matt, Lindsay M. Squeglia, Susan F. Tapert
      Abstract: Substance use (SU) and sleep problems appear interrelated, but few studies have examined the influence of adolescent sleep patterns on development of SU disorders. This study prospectively examined the influence of sleep habits on subsequent SU in youth who later transitioned into heavy drinking. At time 1 (T1), participants (n = 95) were substance-naive 12- to 14-year-olds. Path-analytic models examined whether the effects of T1 risk factors (familial SU disorder, inhibition control, and externalizing and internalizing traits) on time 3 (M = 19.8 years old) tobacco, alcohol, and cannabis were mediated by time 2 (M = 15.1 years old) sleep chronotype, daytime sleepiness, and erratic sleep/wake behaviors. Significant direct path effects of T1 risk factors and time 2 sleep behaviors on time 3 SU were found, Ps 
      PubDate: 2017-05-26T01:51:01.799676-05:
      DOI: 10.1111/adb.12519
  • 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
  • Issue Information
    • Pages: 1117 - 1118
      Abstract: No abstract is available for this article.
      PubDate: 2017-08-28T21:33:15.732407-05:
      DOI: 10.1111/adb.12455
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