Dopaminergic Genetic Variation Influences Aripiprazole Effects on Alcohol Self-Administration and the Neural Response to Alcohol Cues in a Randomized Trial

Abstract

Dopamine (DA) signaling regulates many aspects of Alcohol Use Disorder (AUD). However, clinical studies of dopaminergic medications, including the DA partial agonist aripiprazole (APZ), have been inconsistent, suggesting the possibility of a pharmacogenetic interaction. This study examined whether variation in DA-related genes moderated APZ effects on reward-related AUD phenotypes. The interacting effects of APZ and a variable number tandem repeat (VNTR) polymorphism in DAT1/SLC6A3 (the gene encoding the DA transporter (DAT)) were tested. In addition, interactions between APZ and a genetic composite comprising the DAT1 VNTR and functional polymorphisms in catechol-O-methyltransferase (COMT), DRD2, and DRD4 were evaluated. Ninety-four non-treatment-seeking individuals with AUD were genotyped for these polymorphisms, randomized to APZ (titrated to 15 mg) or placebo for 8 days, and underwent an fMRI alcohol cue-reactivity task (day 7; n=81) and a bar lab paradigm (day 8). Primary outcomes were alcohol cue-elicited ventral striatal (VS) activation and the number of drinks consumed in the bar lab. DAT1 genotype significantly moderated medication effects, such that APZ, relative to placebo, reduced VS activation and bar-lab drinking only among carriers of the DAT1 9-repeat allele, previously associated with lower DAT expression and greater reward-related brain activation. The genetic composite further moderated medication effects, such that APZ reduced the primary outcomes more among individuals who carried a larger number of DAT1, COMT, DRD2, and DRD4 alleles associated with higher DA tone. Taken together, these data suggest that APZ may be a promising AUD treatment for individuals with a genetic predisposition to higher synaptic DA tone.

The dopamine transporter VNTR polymorphism moderates the relationship between acute response to alcohol and future alcohol use disorder symptoms

“…Consistent with these findings, functional neuroimaging studies indicate that individuals who carry the 9R allele, relative to 10R homozygotes, display increased striatal response during the anticipation and receipt of monetary reward . A meta‐analysis of association studies indicated that the 9R allele was associated with a slightly greater likelihood of alcohol dependence, and among individuals with AUD, 9R carriers, relative to 10R homozygotes, self‐administer less alcohol after receiving aripiprazole, a dopamine partial agonist, suggesting that these individuals' drinking is more dopaminergically influenced . Thus, DAT1 VNTR genotype might influence relationships between reward‐related responses to alcohol and subsequent AUD symptoms.…”

Brain region‐specific neuromedin U signalling regulates alcohol‐related behaviours and food intake in rodents

“…Food consumption studies in mice were conducted to evaluate the possibility that different subpopulations of NMUR2, specifically, those in NAc shell, aVTA, and LDTg; modulate food intake; and alcohol‐mediated behaviours. As described previously, the group‐housed mice had unlimited access to chow and peanut butter for 3 days prior to and 4 days after surgery (Crunchy, Green Choice) .…”

A Methodological Checklist for fMRI Drug Cue Reactivity Studies: Development and Expert Consensus

“…J. Moeller et al, 2013;J. P. Schacht et al, 2017;J. P. Schacht, Voronin, Randall, & Anton, 2018;Xu et al, 2013;Yang, Balodis, Lacadie, Xu, & Potenza, 2016).…”