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

Abstract

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. Aims and 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 7 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 coadministration. In contrast, adult females demonstrated an opposing effect in which adolescent cannabinoid and nicotine coexposure resulted in decreased nicotine intake compared with the nicotine only and control groups. Furthermore, after maintaining nicotine self-administration across sessions, pretreatment 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. Implications These studies demonstrate a significant impact of nicotine, cannabinoids, or coexposure on developmental processes during adolescence. Differential effects were observed within each sex, with opposing results found for cannabinoid exposure on nicotine intake in males and females. Intriguingly, we also evidenced resistance to the lowering effects of a cannabinoid agonist on nicotine intake in adulthood based on adolescent drug exposure. Thus, these findings have important implications for our understanding of the impact of nicotine and cannabinoids (eg, Δ9-tetrahydrocannabinol (THC) and synthetic “spice” cannabinoids) during development, with further implications for the effectiveness of therapeutic interventions based on prior drug exposure in youth.

New Insights in the Involvement of the Endocannabinoid System and Natural Cannabinoids in Nicotine Dependence

“…Moreover, THC exposure did not alter relapse to nicotine seeking induced by stress or nicotine-associated cues [ 182 ]. Another study found an increase in nicotine self-administration behavior in adult males at the lower rewarding nicotine dose following adolescent cannabinoid agonist exposure [ 183 ]. The reason for discrepancies in the findings of these studies may result from the different cannabinoid agonists used (THC versus synthetic WIN55,212).…”

Electronic Cigarette Vaping Did Not Enhance the Neural Process of Working Memory for Regular Cigarette Smokers

“…frontal gyrus significantly correlated with the reduced RT for the 3-back task for the r-cig condition only (Ernst et al, 2001b;Lawrence et al, 2002;Xu et al, 2005). Alternatively, ROIs such as the dorsolateral prefrontal cortex and hippocampus in the mesocortical pathway (Zakiniaeiz et al, 2019;Dukes et al, 2020) may also be involved. Thus, the association between the neuronal activations of these candidate ROIs and working memory performance can be investigated.…”

Adult consequences of repeated nicotine and Δ9-tetrahydrocannabinol (THC) vapor inhalation in adolescent rats

“…The lack of difference when the vapor concentration was increased to 60 mg/mL in the PG is perhaps unexpected but the dose-effect curves for intravenous self-administration of nicotine can be quite flat, e.g., across 2-to 3-fold differences in dose. For example, female mice self-administered similar intravenous infusions of nicotine whether it was 0.3 or 0.1 mg/kg/infusion (Dukes et al, 2020) and male rats self-administered similar numbers of intravenous infusions of 0.03 or 0.06 mg/kg/infusion nicotine (O’Dell et al, 2007). It is therefore most likely that the 30 mg/mL and 60 mg/mL conditions used here did not produce a large enough effective difference in delivered dose.…”