ORIGINAL RESEARCH article
Front. Behav. Neurosci.
Sec. Motivation and Reward
This article is part of the Research TopicDrugs of abuse and their endocrine effectsView all articles
Sex, social rank, and nicotine co-administration shape cocaine-and cocaethylene-induced reinstatement in monkeys
Provisionally accepted
- Wake Forest University School of Medicine, Winston-Salem, United States
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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. Socially housed male (N=12) and female (N=10) cynomolgus monkeys, all with experience self-administering cocaine or cocaethylene under a concurrent drug vs. food schedule of reinforcement, were studied after drug choice was extinguished by studying saline vs. food choice (<20% drug choice). 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. Thus, social rank impacted 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.
Keywords: Cocaethylene, Cocaine, drug-food choice, drug-induced reinstatement, Nicotine, nonhuman primates, polysubstance use, relapse
Received: 18 Dec 2025; Accepted: 04 Feb 2026.
Copyright: © 2026 Roberts, Clark, Nader and Rough. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Mia I Rough
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