Interacting Effects of Naltrexone and OPRM I and DAT I Variation on the Neural Response to Alcohol Cues

Variation at a single nucleotide polymorphism in the mu-opioid receptor gene (OPRM I), Al 18G (Asn40Asp), may moderate naltrexone (NTX) effects in alcohol dependence. Both NTX and Al 18G variation have also been reported to affect alcohol cue-elicited brain activation. This study investigated whether sub-acute NTX treatment and Al 18G genotype interacted in their effects on cue-elicited activation of the ventral striatum (VS), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). Secondarily, variation at a variable number tandem repeat polymorphism in the dopamine transporter gene (DAT I/SLC6A3), which has been associated with increased reward-related activation in VS, was analyzed as a moderator of medication and Al 18G effects. Seventy-four non-treatment-seeking alcohol-dependent individuals, half preselected to carry at least one copy of the Al 18G G (Asp) allele, were randomized to NTX (50 mg) or placebo for 7 days, and performed an fMRI alcohol cue reactivity task on day 6. Region-of-interest analyses indicated no main effects of medication or Al 18G genotype. However, these factors interacted in their effects on OFC activation, such that, among NTX-treated individuals, G-allele carriers had less activation than A-allele homozygotes. DAT I variation also moderated medication/Al 18G effects. There was a three-way interaction between medication and Al 18G and DAT I genotypes on VS activation, such that, among G-allele carriers who received NTX, DATI 10-repeat-allele (10R) homozygotes had less activation than 9-repeat-allele (9R) carriers. Further, IOR homozygotes who received NIX had less mPFC activation than 9R carriers. Polymorphic variation in OPRM I and DATI should be considered in future studies of NTX, particularly regarding its effects on reward processing. Neuropsychopharmacology (2013) 38, 414-422; doi:10.1038/npp.2012.195; published online 3 October 2012