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Am J Drug Alcohol Abuse. 2019 Jul 31:1-13. doi: 10.1080/00952990.2019.1638928. [Epub ahead of print]

A role for the CD38 rs3796863 polymorphism in alcohol and monetary reward: evidence from CD38 knockout mice and alcohol self-administration, [11C]-raclopride binding, and functional MRI in humans.

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a Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, NIAAA and NIDA, NIH , Bethesda , MD , USA.
b Laboratory on Neurobiology of Compulsive Behaviors, NIAAA, NIH , Rockville , MD , USA.
c Section on Human Psychopharmacology, NIAAA, NIH , Bethesda , MD , USA.
d Office of the Clinical Director, NIH, NIAAA , Bethesda , MD , USA.
e Clinical NeuroImaging Research Core, NIAAA, NIH , Bethesda , MD , USA.
f Department of Neuroscience, Brown University , Providence , RI , USA.
g BRAIN Laboratory, Department of Psychology, Washington University in St. Louis , St. Louis , MO , USA.
h Psychology Department, University of Sonora , Hermosillo , Sonora , Mexico.
i Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University , Durham , NC , USA.
j Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University , Providence , RI , USA.


Background: Cluster of differentiation 38 (CD38) is a transmembrane protein expressed in dopaminergic reward pathways in the brain, including the nucleus accumbens (NAc). The GG genotype of a common single nucleotide polymorphism (SNP) within CD38, rs3796863, is associated with increased social reward. Objective: Examine whether CD38 rs3796863 and Cd38 knockout (KO) are associated with reward-related neural and behavioral phenotypes. Methods: Data from four independent human studies were used to test whether rs3796863 genotype is associated with: (1) intravenous alcohol self-administration (n = 64, 30 females), (2) alcohol-stimulated dopamine (DA) release measured using 11C-raclopride positron emission tomography (n = 22 men), (3) ventral striatum (VS) response to positive feedback measured using a card guessing functional magnetic resonance imaging (fMRI) paradigm (n = 531, 276 females), and (4) resting state functional connectivity (rsfc) of the VS (n = 51, 26 females). In a fifth study, we used a mouse model to examine whether cd38 knockout influences stimulated DA release in the NAc core and dorsal striatum using fast-scanning cyclic voltammetry. Results: Relative to T allele carriers, G homozygotes at rs3796863 within CD38 were characterized by greater alcohol self-administration, alcohol-stimulated dopamine release, VS response to positive feedback, and rsfc between the VS and anterior cingulate cortex. High-frequency stimulation reduced DA release among Cd38 KO mice had reduced dopamine release in the NAc. Conclusion: Converging evidence suggests that CD38 rs3796863 genotype may increase DA-related reward response and alcohol consumption.


CD38; alcohol; dopamine; genetics; knockout; nucleus accumbens; reward; ventral striatum

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