β-Caryophyllene, a Dietary Terpenoid, Inhibits Nicotine Taking and Nicotine Seeking in Rodents

Background And Purpose: β-Caryophyllene (BCP) is a plant-derived terpenoid used as a food additive for many decades. Recent studies indicate that BCP is a cannabinoid CB receptor agonist with medical benefits for a number of human diseases. However, little is known about its therapeutic potential for drug abuse and addiction.

Experiment Approach: We used pharmacological, transgenic, and optogenetic approaches to systematically evaluate the effects of BCP on nicotine-taking and nicotine-seeking behaviour in animal models of drug self-administration, electrical, and optical brain-stimulation reward.

Key Results: Systemic administration of BCP dose-dependently inhibited nicotine self-administration and motivation for nicotine seeking in rats and mice. The reduction in nicotine self-administration was blocked by AM630, a selective CB receptor antagonist, but not by AM251, a selective CB receptor antagonist, suggesting involvement of a CB receptor mechanism. Genetic deletion of CB receptors in mice blocked the reduction in nicotine self-administration produced only by low doses, but not by high doses, of BCP, suggesting involvement of both CB and non-CB receptor mechanisms. Furthermore, in the intracranial self-stimulation paradigm, BCP attenuated electrical brain-stimulation reward and nicotine-enhanced brain-stimulation reward in rats. Lastly, BCP also attenuated brain-stimulation reward maintained by optogenetic stimulation of dopaminergic neurons in the ventral tegmental area in DAT-cre mice, suggesting the involvement of a dopamine-dependent mechanism in BCP's action.

Conclusions And Implications: The present findings suggest that BCP has significant anti-nicotine effects via both CB and non-CB receptor mechanisms and, therefore, deserves further study as a potential new pharmacotherapy for cigarette smoking cessation.