Sex, social rank, and nicotine co-administration shape cocaine- and cocaethylene-induced reinstatement in monkeys.

Introduction: Cocaine use disorder (CUD) is highly comorbid with alcohol and nicotine use, yet preclinical research rarely models polysubstance use or incorporates clinically relevant variables such as social and biological factors. This study utilized an animal model of relapse, cocaine-induced reinstatement, under a drug vs. food choice procedure; the effect of co-use of nicotine was also examined. Cocaethylene, the active metabolite formed when alcohol and cocaine are co-used, was also examined with and without nicotine co-use. Methods: Socially housed male ( Results: In Experiment 1, both cocaine (0.01-0.3 mg/kg, i.v.) and cocaethylene (0.03-0.3 mg/kg, i.v.) pretreatments reliably increased drug-associated choice; dominant monkeys of both sexes showed greater reinstatement following cocaine and cocaethylene pretreatments when compared to subordinates. Cocaine was also more potent than cocaethylene regardless of sex or social rank. In Experiment 2, nicotine (0.01-0.056 mg/kg) was co-administered with saline, cocaine or cocaethylene. Nicotine alone increased drug-associated choice only in females and selectively increased cocaine-induced drug-associated choice only in females, regardless of social rank. Nicotine did not significantly alter cocaethylene-induced reinstatement, although a trending increase was observed in females. Discussion: Thus, social rank impacts cocaine- and cocaethylene-induced reinstatement, and the effects of nicotine were influenced by sex. This underscores the value of translational models that move beyond single-drug approaches and suggest that especially in women with CUD, abstaining from nicotine would increase the likelihood of remaining abstinent from cocaine.