This study will elucidate the pharmacogenetic effects of the Asn40Asp SNP of the OPRM1 gene on biobehavioral and neural markers of response to naltrexone in individuals of East Asian descent, an ethnic group most likely to express the positive predictive allele.

Recent pharmacogenetic studies have advanced the gene coding for µ-opioid receptors (OPRM1) gene as a potential moderator of responses to naltrexone. The most widely studied polymorphism of the OPRM1 gene is the Asn40Asp single nucleotide polymorphism (SNP), a functional mutation thought to affect receptor activity such that the Asp40 variant binds β-endorphin three times stronger than the Asn40 allele. Recent studies have found that Asp40 carriers have a stronger striatal dopamine response to intravenous alcohol administration and report stronger feelings of alcohol reward. Findings from the COMBINE Study demonstrated that if treated with Medication Management alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of Asn40 homozygotes. While these findings are promising, studies have also highlighted allele frequency imbalance as a function of ethnicity such that the Asp40 allele frequency is approximately 20% in Caucasians, 5% in individuals of African Ancestry, and as high as 50% among individuals of East Asian descent. Therefore, to the extent to which this SNP moderates behavioral and clinical responses to NTX, ethnicity must be carefully considered in order to extend the findings from primarily Caucasian samples to ethnic minorities, such as Asian Americans. Preliminary work by our team has found that among individuals of East Asian descent, Asp40 carriers show greater NTX-induced blunting of alcohol craving as well as potentiation of the aversive effects of alcohol. This pilot study also found support for a gene dose-response, such that Asp40Asp individuals showed greater NTX responsivity than those with the Asn40Asp genotype. This study seeks to build upon these preliminary findings by testing heavy drinkers of East Asian descent across three OPRM1 genotypes (Asn40Asn, n = 30; Asn40Asp, n = 30, and Asp40Asp, n = 30). Participants will complete two double-blinded, counterbalanced alcohol infusion and self-administration sessions, one after taking NTX (50 mg/day) and one after taking matched placebo for five days. In each medication condition, participants will complete a functional neuroimaging task examining cue-induced craving for alcohol. This study will elucidate the pharmacogenetic effects of the Asn40Asp SNP of the OPRM1 gene on biobehavioral and neural markers of response to naltrexone in individuals of Asian descent, an ethnic group most likely to express the positive predictive allele (Asp40). The long-term objective of this research is to optimize alcoholism pharmacotherapy and to address health disparities by advancing pharmacogenetic studies in ethnic minority groups.

Inclusion Criteria:

• current (i.e., past month) alcohol dependence
• East Asian ethnicity (i.e., Chinese, Korean, or Japanese)
• Prospective genotyping for the A118G SNP of the mu opioid receptor (OPRM1) gene to allow for balanced groups on all three genotypes (AA, AG, GG)

Exclusion Criteria:

• lifetime DSM-IV of drug dependence (other than alcohol or nicotine)
• current use of psychoactive drugs as determined by self-reports and verified using toxicology testing
• lifetime diagnosis of bipolar disorder or any psychotic disorder
• contraindications to an MRI scan (including left handedness)

Providing baseline data for the 77 individuals who completed at least one experimental session

Adverse event data were collected immediately prior to alcohol infusion while on naltrexone and while on placebo (2 time points). This data was collected twice for each participant, once while they were on placebo and once while they were on naltrexone.

Adverse events are defined as any symptom endorsed on the Side Effects Checklist (SAFTEE). The instructions on the SAFTEE are, "Have you noticed any of the following symptoms within the last 6 hours? If yes, how severe were the symptoms? Do you believe these symptoms were caused by the study medication?"