Naltrexone has reduced craving and relapse in some, but not all, alcoholics. One potential variable thatmight predict naltrexone, and potentially other opiate antagonist responses, is a difference in a singlenucleotide substitution in the mu opiate receptor protein that makes that receptor respond differently toendogenous beta-endorphin as well as to exogenous opiate antagonists like naltrexone. An (A)denine to(G)uanine substitution at position 118 (A118G) in the coding region of the mu opiate receptor accounts foran asparagines (asn) to aspartate (asp) amino acid substitution at position 40 (asn40asp) in the receptorprotein that occurs in about 15% of the population. The purpose of this1 proposal is to examine the role ofthis allelic difference in naltrexone responsivity in a well-established sub-acute dosing, brain imaging, andbar-lab paradigm. Interaction with another functional allele difference (va!158met substitution) in catechol-omethyl-transferase (COMT), an enzyme that controls CNS dopamine tone, will be explored.Three hundred non-treatment seeking alcoholics will be assessed and subtyped for mu opiate receptorand COMT allelic variants. Eighty individuals (40 with the more common AA gene and 40 with either an AGor GG gene) will be randomly assigned to take either naltrexone (50 mg/day) or a matching placebo for 7days. Val and Met alleles of the COMT gene will be equally distributed by urn randomization to all groups.After 5 days of natural drinking and one day of abstinence, subjects will undergo an alcohol cue-inducedfMRI brain scan on day 6 of study drug. On day 7, after a standard alcohol drink, stimulation, sedation,intoxication, and craving will be evaluated over 40 minutes. Then subjects may choose to drink up to 8 minidrinksover a 2-hour period.It is hypothesized that when taking naltrexone, AG/GG (40asp) subjects compared to subjects with theAA (40asn) will show a greater reduction of cue-induced brain stimulation in the nucleus accumbens, lessalcohol induced stimulation, and less free choice drinking. Those with both the asn40asp and val158metsubstitutions could have the strongest responses to naltrexone. This data will provide support for the use ofgenotyping in predicting which treatment seeking alcoholic will or will not respond to naltrexone. Also, thiswork brings pharmacogenetics to our Center for future medication/gene interaction studies.
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