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

Neuropsychopharmacology. 2018 May;43(6):1247-1256. doi: 10.1038/npp.2017.298. Epub 2017 Dec 6.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alcohol Deterrents / therapeutic use*
  • Alcohol Drinking / drug therapy
  • Alcohol Drinking / genetics
  • Alcohol Drinking / physiopathology
  • Alcoholism / diagnostic imaging
  • Alcoholism / drug therapy*
  • Alcoholism / genetics*
  • Alcoholism / physiopathology
  • Aripiprazole / therapeutic use*
  • Brain / diagnostic imaging
  • Brain / physiopathology
  • Catechol O-Methyltransferase / genetics
  • Central Nervous System Depressants / administration & dosage
  • Craving / drug effects
  • Craving / physiology
  • Cues
  • Dopamine Agonists / therapeutic use*
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Ethanol / administration & dosage
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Minisatellite Repeats
  • Motivation / drug effects
  • Motivation / genetics
  • Motivation / physiology
  • Pharmacogenomic Variants
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D4 / genetics
  • Self Administration


  • Alcohol Deterrents
  • Central Nervous System Depressants
  • DRD2 protein, human
  • DRD4 protein, human
  • Dopamine Agonists
  • Dopamine Plasma Membrane Transport Proteins
  • Receptors, Dopamine D2
  • SLC6A3 protein, human
  • Receptors, Dopamine D4
  • Ethanol
  • Aripiprazole
  • COMT protein, human
  • Catechol O-Methyltransferase