A genetic determinant of the striatal dopamine response to alcohol in men

Abstract

Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [11C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a four-fold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.

GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol

“…Microdialysis evaluations of ethanol-induced increases in NAc DA levels were performed following previously described procedures (68). Data were collected from two independent cohorts (cohort 5: WT, n = 8; KO, n = 9; cohort 6: WT, n = 8; KO, n = 8) and pooled together, because there was no significant difference between baseline NAc DA level and ethanol effect for each genotype between the two cohorts.…”

Neuroimaging in Psychiatric Pharmacogenetics Research: The Promise and Pitfalls

“…In contrast, genes associated with lower synaptic dopamine concentrations and normal dopamine receptor and transporter function are associated with greater smoking-induced dopamine release; subjects carrying at least one DAT1 9R allele, o7-repeats of the DRD4 VNTR, or who were homozygous for the COMT val allele showed a greater change in [ 11 C]raclopridebinding potential in the ventral caudate and nucleus accumbens after smoking a cigarette (Brody et al, 2006). Genetic variation in the mu-opioid receptor, which has downstream effects on dopamine release, is also related to dopamine release following an alcohol challenge (Ramchandani et al, 2011).…”

Opioid pharmacogenetics of alcohol addiction

“…There was a blunted locomotor response to morphine in the 112G mice, as well as decreased morphine conditioned place preference (CPP) in 112G female mice, the latter being a sexually dimorphic response, with 112G males showing the expected CPP response to morphine. Two other forms of transgenic mice were produced, using homologous recombination to replace the murine OPRM1 exon 1 with one of the two forms (118A and 118G) of human OPRM1 exon 1 (Ramchandani et al 2010). These investigators conducted in vivo microdialysis experiments in the ventral striatum, demonstrating that the 118G mice had the expected elevations in dopamine release after alcohol, whereas the 118A mice had no significant increase over baseline (see AA and AG group figures in Ramchandani et al 2011).…”

“…Two other forms of transgenic mice were produced, using homologous recombination to replace the murine OPRM1 exon 1 with one of the two forms (118A and 118G) of human OPRM1 exon 1 (Ramchandani et al 2010). These investigators conducted in vivo microdialysis experiments in the ventral striatum, demonstrating that the 118G mice had the expected elevations in dopamine release after alcohol, whereas the 118A mice had no significant increase over baseline (see AA and AG group figures in Ramchandani et al 2011). These data suggest that the "G" allele conveys an increased rewarding valence to alcohol, compared to the "A" allele.…”