ALCOHOL CUES AND THE VENTRAL STRIATUM: PHARMACOGENETIC MODERATION OF NALTREXONE EFFECTS AND PREDICTION OF TREATMENT RESPONSE

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Schacht JP1, Myrick H1,2, Latham PK1, Voronin KE1, Anton RF1

1Medical University of South Carolina, Charleston, SC, USA
2Ralph H. Johnson VA Medical Center, Charleston, SC, USA

A number of neuroimaging studies have investigated the effects of naltrexone and of variation at the OPRM1 A118G single nucleotide polymorphism on the neural response to alcohol cues, but it is unclear whether these factors interact in their effects on alcohol cue-elicited brain activation in a manner similar to that reported in clinical trials of naltrexone (e.g., greater response among A118G G-allele carriers). We conducted two studies in which individuals with alcohol dependence of increasing severity were prospectively randomized to naltrexone or placebo on the basis of their A118G genotype and scanned with an fMRI alcohol cue reactivity task. In the first study, 74 non-treatment-seeking alcoholics were scanned after 6 days on medication. There were no main effects of naltrexone or OPRM1 genotype on cue-elicited brain activation, but there was an interaction between these factors and variation at a variable number tandem repeat polymorphism in the dopamine transporter gene (DAT1) on cue-elicited activation of the ventral striatum, such that the predicted greater effect of naltrexone among G-allele carriers was present only among individuals who also carried the DAT1 10-repeat allele, which has been associated with relatively lower ventral striatal dopamine tone. In the second study, 132 treatment-seeking alcoholics were scanned immediately before beginning a 16-week medication trial and again after 14 days on medication. Naltrexone reduced cue-elicited ventral striatal activation after 14 days. Its effect was greatest among individuals with greater baseline activation and among those who were abstinent from alcohol between scans. In contrast to the first study, there was no interaction between medication and OPRM1 or DAT1 genotypes on cue-elicited ventral striatal activation. Individuals with greater baseline activation of the ventral striatum and medial prefrontal cortex who received naltrexone had significantly less heavy drinking, relative to those with lower baseline activation and those who received placebo, over the course of treatment. Collectively, these data indicate subgroups that may respond better to naltrexone (e.g., individuals with certain genotype combinations, those able to abstain early in treatment, and those who are particularly responsive to alcohol cues at treatment initiation), and suggest that disease severity may differentially affect these prognostic factors.

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