Adolescent Cannabinoid and Nicotine Exposure Differentially Alters Adult Nicotine Self-Administration in Males and Females.

INTRODUCTION: During adolescence, exposure to nicotine or cannabis independently induces effects on neuromaturation and later cognitive function. However, the potential effect of both drugs under co-use conditions has become of increasing concern given the prevalence of e-cigarettes, legalization of cannabis, and availability of synthetic 'spice' cannabinoid agonists. METHODS: The current studies investigated the effects of exposure to a cannabinoid receptor agonist (WIN55-212,2) and/or nicotine over a discrete time period in mid-adolescence on later intravenous nicotine self-administration in adult male and female mice. We further examined whether cannabinoid agonist administration in adulthood would alter nicotine reinforcement, with either acute or chronic pairing across seven days. RESULTS: We found that adult males exhibited increased nicotine self-administration at a lower, rewarding nicotine dose following adolescent cannabinoid exposure, either alone or with nicotine co-administration. In contrast, adult females demonstrated an opposing effect in which adolescent cannabinoid and nicotine co-exposure resulted in decreased nicotine intake compared to the nicotine only and control groups. Furthermore, after maintaining nicotine self-administration across sessions, pre-treatment with a low dose of the cannabinoid agonist decreased nicotine intake in both male and female control mice, and this lowering effect was evidenced after both acute and chronic treatment. However, the cannabinoid agonist was ineffective in altering nicotine intake in mice previously exposed to nicotine, cannabinoid agonist, or both during adolescence. CONCLUSIONS: These data provide evidence that adolescent drug exposure can alter later nicotine reinforcement in a sex-specific manner and can further modulate the effectiveness of interventions in reducing nicotine intake during adulthood.