Effects of nicotinic receptor antagonism on nicotine and THC self-administration in a model of polysubstance use

Abstract Background Most substance users are polysubstance users; however, little is known about how the combined use of different drugs affects the course of substance use disorder or effectiveness of treatment. Notably, co-use of cannabis and nicotine is very common, and we previously demonstrated that nicotine enhances the self-administration of a synthetic cannabinoid receptor agonist and the primary psychoactive phytocannabinoid in cannabis, Δ-9-tetrahydrocannabinol (THC).

Methods: Here we aimed to further investigate the patterns of nicotine and THC self-administration when available in a concurrent choice model, and to determine the effects of nicotinic acetylcholine receptor (nAchR) antagonists on nicotine-enhanced THC self-administration in male and female rats.

Results: During concurrent choice, nicotine availability increased THC self-administration in females without affecting THC metabolism, while THC availability decreased nicotine self-administration and preference in females relative to when nicotine and saline were concurrently available. In females, THC self-administration was reduced by the α4β2/4 subunit-containing nAchR antagonist dihydro-beta-erythroidine in both nicotine and saline concurrent availability groups; while nicotine self-administration was reduced in both sexes by the α7nAchR antagonist methylylcaconitine, but only in rats that had concurrent access to THC. The nonspecific nAchR antagonist mecamylamine had minimal effects in the concurrent choice model, but it prevented nicotine-induced enhancement of THC self-administration when nicotine was given prior to a single choice THC only self-administration session.

Conclusions: Thus, behavioral regulation of self-administration is differentially influenced by nAchR subtypes depending on the availability of other substances, which has implications for the efficacy of treatments in the context of polysubstance use. Significance statement Polysubstance use is extremely common, but very understudied in both clinical and preclinical research. The results presented here highlight that pharmacological modulators of drug reinforcement can differ when multiple drugs are available simultaneously, highlighting the importance of investigating potential treatments for substance use disorders in the context of polysubstance use.