Suppression of alcohol preference by naltrexone in the rhesus macaque: a critical role of genetic variation at the micro-opioid receptor gene locus.
BACKGROUND
The role of a nonsynonymous A118G polymorphism of the human micro-opioid receptor gene (OPRM1) for alcohol reward and therapeutic efficacy of naltrexone remains controversial. A functionally equivalent OPRM1 C77G polymorphism in rhesus macaques allows this to be addressed under controlled experimental conditions.


METHODS
Twenty-one rhesus macaques (13 female rhesus macaques, 8 male rhesus macaques) were genotyped for OPRM1 C77G and studied during 1-hour sessions for preference between an aspartame-sweetened alcohol solution (8.4% vol/vol) and a nonalcoholic control fluid in a baseline session followed by naltrexone (1 mg/kg) and vehicle treatment in a counterbalanced within-subject design.


RESULTS
Mixed-model analysis of variance controlling for baseline and sex showed a highly significant (p = .003) interaction between genotype and treatment. Post hoc analysis showed that vehicle-treated 77G carriers had markedly higher alcohol preference than 77C homozygous subjects (p = .001). Following naltrexone administration, 77G carriers decreased their preference (p = .002) and no longer differed from 77C homozygous subjects. In contrast, the latter group was unaffected by treatment and, in fact, showed a trend-level increase of preference following naltrexone.


CONCLUSIONS
These results support a critical pharmacogenetic role of OPRM1 variation for therapeutic efficacy of naltrexone.
Barr
Christina S
CS
Laboratory of Clinical and Translational Studies, National Institutes of Health (NIH)/National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, Maryland 20892-1108, USA.
Chen
Scott A
SA
Schwandt
Melanie L
ML
Lindell
Stephen G
SG
Sun
Hui
H
Suomi
Stephen J
SJ
Heilig
Markus
M
D000437:Alcoholism / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics*; D000818:Animals; D001218:Aspartame / Q000008:administration & dosage; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005518:Food Preferences / Q000187:drug effects* / Q000502:physiology; D008253:Macaca mulatta; D008297:Male; D009271:Naltrexone / Q000494:pharmacology* / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017450:Receptors, Opioid, mu / Q000235:genetics*; D013549:Sweetening Agents / Q000008:administration & dosage
D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D013549:Sweetening Agents; D009271:Naltrexone; D001218:Aspartame