β-Caryophyllene, a dietary terpenoid, inhibits nicotine taking and nicotine seeking in rodents

β-Caryophyllene (BCP) is a plant-derived terpenoid used as a food additive for many decades. Recent studies indicate that BCP is a cannabinoid CB₂ receptor agonist with medical benefits for a number of human diseases. However, little is known about its therapeutic potential for drug abuse and addiction.

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.

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 CB₂ receptor antagonist, but not by AM251, a selective CB₁ receptor antagonist, suggesting involvement of a CB₂ receptor mechanism. Genetic deletion of CB₂ 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 CB₂ and non-CB₂ 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.

The present findings suggest that BCP has significant anti-nicotine effects via both CB₂ and non-CB₂ receptor mechanisms and, therefore, deserves further study as a potential new pharmacotherapy for cigarette smoking cessation.