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

Abstract

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 2 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 2 receptor antagonist, but not by AM251, a selective CB 1 receptor antagonist, suggesting involvement of a CB 2 receptor mechanism. Genetic deletion of CB 2 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 2 and non-CB 2 receptor mechanisms. Furthermore, in the intracranial self-stimulation paradigm, BCP attenuated electrical brain-stimulation reward and nicotine-enhanced brainstimulation 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 2 and non-CB 2 receptor mechanisms and, therefore, deserves further study as a potential new pharmacotherapy for cigarette smoking cessation.

β-caryophyllene, an FDA-Approved Food Additive, Inhibits Methamphetamine-Taking and Methamphetamine-Seeking Behaviors Possibly via CB2 and Non-CB2 Receptor Mechanisms

“…Notably, BCP, at a high dose (100 mg/kg), also inhibited METH self-administration in CB2-KO mice, suggesting that non-CB2 receptor mechanisms are involved in high dose BCP-mediated effects. This is consistent with our previous reports that systemic administration of BCP, at high doses (50, 100 mg/kg), also inhibits cocaine or nicotine self-administration in CB2-KO mice ( He et al, 2020 ; Galaj et al, 2021 ), suggesting that BCP’s selectivity as a CB2 receptor agonist depends on the BCP dose, and at high doses, it also binds to other (non-CB2) receptors. Furthermore, BCP alone did not produce a significant decrease in extracellular NAc DA, while pretreatment with BCP dose-dependently attenuated METH-induced increase in extracellular DA, suggesting that a DA-dependent mechanism at least in part underlies BCP’s actions against METH.…”

“…BCP was obtained from MilliporeSigma (Burlington, MA, United States) and dissolved in 5% Kolliphor EL (i.e., Cremophor) (BASF Pharma, Ludwigshafen, Germany). The BCP doses were chosen from our previous reports ( Galaj and Xi, 2020 ; He et al, 2020 ). AM630 was purchased from Tocris Division of Bio-Techne (Minneapolis, MN, United States) and dissolved in saline; the doses of AM630 (3, 10 mg/kg) were chosen based on our previous experiments ( Galaj and Xi, 2020 ).…”

“…BCP has been shown to exhibit its anti-inflammatory, antioxidant, antiviral, and analgesic effects ( Cho et al, 2007 ; Gertsch et al, 2008 ; Katsuyama et al, 2013 ; Chicca et al, 2014 ; Guo et al, 2014 ; Klauke et al, 2014 ; Fidyt et al, 2016 ). Recently, BCP has been found to confer protection against various diseases, including cerebral ischemic injury ( Chang et al, 2013 ), anxiety and depressive disorders ( Bahi et al, 2014 ), alcohol use disorder ( Al Mansouri et al, 2014 ), nicotine dependence ( He et al, 2020 ) and cocaine abuse ( Galaj et al, 2021 ). However, it is unknown whether BCP is also effective against METH reward, intake, and relapse.…”

Selective activation of cannabinoid receptor 2 regulates Treg/Th17 balance to ameliorate neutrophilic asthma in mice

“…In recent years, β-Car at low concentration exerted promising protective effects that could be considered for the treatment of neurodegenerative disorders such as multiple sclerosis (33). He et al (34) proposed that β-Car could be a potential new pharmacotherapy for cigarette smoking cessation because of its significant anti-nicotine effects via both CB2 and non-CB2 receptor mechanisms. In the present study, β-Car improved the infiltration of inflammatory cells in the lung tissue exposed to cigarette smoking, and decreased cell accumulation in the neutrophilic asthmatic mice.…”

Cannabinoid-2 Agonism with AM2301 Mitigates Morphine-Induced Respiratory Depression

“…Cannabinoids and respiration THC (1, 10 mg/kg, i.p., N = 9/group), a mixed CB1R/CB2R agonist, doses were chosen based on published reports. [31][32][33] THC was compared with vehicle and was significant for a factor of dose (F[2,52] = 4.245, p = 0.0196). THC 1, p > 0.9999 under both conditions, and 10 mg/kg, p = 0.4098, did not significantly decrease frequency of respirations, or BPM, under the 0% CO 2 condition ( Fig.…”