A pharmacogenetic model of naltrexone-induced attenuation of alcohol consumption in rhesus monkeys.
BACKGROUND
Variation at the human mu-opioid receptor has been associated with alcohol abuse. The A118G (N40D) polymorphism in humans is functionally mimicked by the C77G (P26R) polymorphism in rhesus monkeys; both show similar in vitro influences on ligand binding and in vivo correlations with physiological measures as well as behavioral measures including predilection towards alcohol consumption. Naltrexone, an antagonist at the receptor, has been used to treat alcoholism in humans and has been reported to show differences in effectiveness depending on genotype.


METHODS
Here we describe a study in which we a priori selected rhesus monkeys based on genotype at the OPRM1 C77G single nucleotide polymorphism, trained them to self-administer alcohol, and assessed naltrexone responsiveness.


RESULTS
Alcohol intake in rhesus monkeys varied with genotype across a range of alcohol concentrations (0.5-4%, w/v) such that animals with the G/G genotype drank consistently more alcohol than those animals with the C/C genotype. Additionally, naltrexone attenuated alcohol drinking in a dose- and genotype-dependent manner. Animals harboring the G/G genotype were more sensitive to the effects of naltrexone and showed greater reductions in alcohol consumption at lower naltrexone doses compared to animals with a C/G or C/C genotype.


CONCLUSIONS
This preliminary study demonstrates a pharmacogenomic response to naltrexone in rhesus monkeys that parallels that seen in humans. This finding provides a basis for developing a pharmacogenetic animal model for naltrexone effect that can expand further our understanding of the causes and treatments of alcohol use disorders.
Vallender
Eric J
EJ
New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, Southborough, MA 01772, USA.
Rüedi-Bettschen
Daniela
D
Miller
Gregory M
GM
Platt
Donna M
DM
D000428:Alcohol Drinking / Q000188:drug therapy* / Q000235:genetics* / Q000523:psychology; D000818:Animals; D002492:Central Nervous System Depressants / Q000097:blood / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000097:blood / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D005838:Genotype; D008253:Macaca mulatta; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D017450:Receptors, Opioid, mu / Q000235:genetics*; D012055:Reinforcement Schedule
D002492:Central Nervous System Depressants; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D000431:Ethanol; D009271:Naltrexone