Impact of OPRM1 (Mu-opioid Receptor Gene) A112G Polymorphism on Dual Oxycodone and Cocaine Self-administration Behavior in a Mouse Model

use of mu-opioid receptor (MOP-r) agonists such as oxycodone together with cocaine is prevalent, and deaths attributed to using these combinations have increased. Rationale: It is unknown if functional single nucleotide polymorphisms (SNPs), such as the OPRM1 (MOP-r gene) SNP A118G, can predispose individuals to more dual opioid and psychostimulant intake. The dual self-administration (SA) of MOP-r agonists and cocaine has not been thoroughly examined, especially with regard to neurobiological changes. Objectives: We examined oxycodone SA and subsequent dual oxycodone and cocaine SA in male and female A112G (A/G and G/G, heterozygote and homozygote, respectively) mice, models of human A118G carriers, versus wild -type (A/A) mice. Methods: Adult male and female A/G, G/G and A/A mice self-administered oxycodone (0.25 mg/kg/infusion, 4hr/session, FR 1.) for 10 consecutive days (sessions 1-10). Mice then self-administered cocaine (2 hr) following oxycodone SA (4 hr, as above) in each session for a further 10 consecutive days (sessions 11-20). Message RNA transcripts of 24 reward-related genes were examined in the dorsal striatum. Results: Male and female A/G and G/G mice had greater oxycodone SA than A/A mice did in the initial 10 days and in the last 10 sessions. Further, A/G and G/G mice showed greater cocaine intake than A/A mice. Dorsal striatal mRNA levels of Pdyn, Fkbp5, Oprk1, and Oprm1 were altered following oxycodone and cocaine SA. Conclusions: These studies demonstrated that this functional genetic variation in Oprm1 affected dual opioid and cocaine SA and altered specific gene expression in the striatum.(c) 2024 IBRO. Published by Elsevier Inc. All rights reserved.