Polydrug Abuse: Opioid-Alcohol Combinations - Polydrug use refers to the use of two or more substances on the same occasion or on separate but recent occasions. One of the most common polydrug combinations reported in opioid users is the combination of an opioid with alcohol. Unfortunately, combinations of opioids and alcohol are associated with a number of significant negative outcomes including higher fatality rates, higher relapse rates to both alcohol and opioids, and poorer treatment outcomes. There is a clear need to better understand the combined effects of opioids with alcohol at the behavioral level, and to begin to probe influencing factors. Both illicit and clinically useful opioids exert their behavioral effects primarily through binding at and stimulation of mu opioid receptors (MORs). Notably, some of the behavioral effects of alcohol also can be attributed to the stimulation of MORs. Considerable evidence suggests that a functional variant of the human MOR (OPRM1 A118G) may be associated with increased sensitivity to the behavioral effects of both opioids and alcohol. It is logical, then, to assume that this same single nucleotide polymorphism may influence the behavioral response to opioid-alcohol combinations. This proposal capitalizes on our access to rhesus monkeys that have been genotyped for an orthologous MOR single nucleotide polymorphism (C77G) that results in a variant of the rhesus monkey MOR that appears to have many of the same functional, physiological and behavioral consequences as the human polymorphism. We will use these animals to evaluate the hypothesis that MOR neurogenetic variation contributes to individual differences in the reinforcing effects of alcohol, opioids and their combination and is a key contributor to vulnerability to combined opioid-alcohol taking. Using an established oral alcohol self- administration procedure, Specific Aim 1 will test the hypothesis that the C77G polymorphism influences the reinforcing effects of alcohol alone. Using a new oral oxycodone self-administration procedure, Specific Aim 2 will evaluate the hypothesis that this polymorphism influences the reinforcing effects of oxycodone alone. Finally, Specific Aim 3 will assess the hypothesis that the C77G polymorphism will influence the reinforcing effects of oral oxycodone-alcohol combinations. In all aims, a novel behavioral economic analysis will be used to rigorously evaluate the reinforcing effectiveness of the individual drugs and drug combinations in the two genotypes. Specifically, we predict that individuals homozygous for the functional variant (i.e., GG subjects) will self- administer the component drugs and drug combinations to a greater degree and will be more resistant to behavioral manipulations designed to reduce drug taking (i.e., increases in price). Our results will provide novel data regarding the contribution of genetic variance in OPRM1 to individual differences in the reinforcing effects of opioids, alcohol and opioid-alcohol combinations. Ultimately, our findings can be leveraged to target prevention and treatment strategies to specific individuals at greatest risk for developing opioid, alcohol, and/or polydrug use disorders.
