Genetic moderators of naltrexone's effects on alcohol cue reactivity.
BACKGROUND
Naltrexone (NTX) reduces drinking and craving in alcoholic individuals in treatment and also in heavy drinkers. Polymorphisms in the D4 dopamine receptor (DRD4) gene and mu-opiate receptor gene (OPRM1) may moderate NTX's effects on craving. This study examined these candidate genes as moderators of the effects of NTX on cue-elicited urge to drink in non-treatment-seeking heavy drinkers.


METHODS
Data from the subset of 93 participants who consented for genetic testing in a larger study of medication effects were used to examine pharmacogenetic hypotheses. The non-treatment-seeking male and female heavy drinkers (62% alcohol dependent) were genotyped for the variable number of tandem repeats polymorphism in the DRD4 gene [L=7 or more (n=34), S=less than 7 (n=56)] and Asn40Asp single-nucleotide polymorphism in the OPRM1 gene [29 aspartate (Asp) carriers and 59 asparagine (Asn) homozygotes]. Ten days after randomization to NTX (50 mg) or placebo, participants completed an alcohol cue reactivity assessment.


RESULTS
Any medication effects were all accounted for by interaction with genotype. Naltrexone increased urge for alcohol in Asp carriers across alcohol and neutral beverage cue trials and had no effect on homozygous Asn carriers. Asp40 carriers on either medication had greater decreases (from resting baseline) in mean arterial blood pressure across all beverage cue trials compared with Asn carriers. For DRD4, no differential medication effects by DRD4 polymorphism were found. Alcohol dependence diagnosis did not moderate the effects of gene and medication on cue-elicited measures.


CONCLUSIONS
The differential responses to NTX due to variation in the OPRM1 gene may help explain conflicting results in clinical trials and suggest directions for patient-treatment matching.
McGeary
John E
JE
Center for Alcohol and Addiction Studies, Brown University, Providence, Rhode Island 02906, USA. John_McGeary@brown.edu
Monti
Peter M
PM
Rohsenow
Damaris J
DJ
Tidey
Jennifer
J
Swift
Robert
R
Miranda
Robert
R
D000293:Adolescent; D000328:Adult; D000428:Alcohol Drinking / Q000188:drug therapy / Q000235:genetics* / Q000523:psychology; D000437:Alcoholism / Q000188:drug therapy / Q000235:genetics* / Q000523:psychology; D000704:Analysis of Variance; D016009:Chi-Square Distribution; D003463:Cues; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D009271:Naltrexone / Q000494:pharmacology / Q000627:therapeutic use*; D050638:Receptors, Dopamine D4 / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics
C493599:DRD4 protein, human; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D050638:Receptors, Dopamine D4; D000431:Ethanol; D009271:Naltrexone