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

ABSTRACT

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.

KEYWORDS:

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

Acknowledgements

The authors would like to thank the clinical and research staff involved in data collection and support at the National Institutes of Health (NIH) Intramural Research Program, in particular clinical and research staff in the NIAAA Division of Intramural Clinical and Biological Research, and at the NIH Clinical Center.

Disclosure statement

The authors declare no conflict of interest.

Supplementary Material

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Additional information

Funding

This work was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research (MRL, JHS, SD, AMD, BLS, JY, VAR, MLS, ENG, RM, VAA, LL), National Institute on Drug Abuse Intramural Research Program (MRL, SD, AMD, LL) and the National Institute of Neurological Disorders and Stroke Division of Intramural Research (JHS, VAA). The development of the Computerized Alcohol Infusion System (CAIS) software used in the IV-ASA study was supported by the NIAAA-funded Indiana Alcohol Research Center [AA007611]. The Duke Neurogenetics Study is supported by Duke University and the National Institutes of Health [NIDA R01-DA033369]. ARH receives additional support from the National Institutes of Health [NIDA R01-DA031579]. NCS was supported by NIMH [T32-MH014677]. RB was supported by the Klingenstein Third Generation Foundation and receives additional support from the National Institutes of Health [NIA R01-AG045231].