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

Xiang-Hu He,Yi He,Guo-Hua Bi,Eliot L Gardner,Ewa Galaj,Zheng-Xiong Xi,Briana Hempel,Yan-Lin Wang

doi:10.3389/fphar.2021.722476

Abstract

Recent research indicates that brain cannabinoid CB2 receptors are involved in drug reward and addiction. However, it is unclear whether β-caryophyllene (BCP), a natural product with a CB2 receptor agonist profile, has therapeutic effects on methamphetamine (METH) abuse and dependence. In this study, we used animal models of self-administration, electrical brain-stimulation reward (BSR) and in vivo microdialysis to explore the effects of BCP on METH-taking and METH-seeking behavior. We found that systemic administration of BCP dose-dependently inhibited METH self-administration under both fixed-ratio and progressive-ratio reinforcement schedules in rats, indicating that BCP reduces METH reward, METH intake, and incentive motivation to seek and take METH. The attenuating effects of BCP were partially blocked by AM 630, a selective CB2 receptor antagonist. Genetic deletion of CB2 receptors in CB2-knockout (CB2-KO) mice also blocked low dose BCP-induced reduction in METH self-administration, suggesting possible involvement of a CB2 receptor mechanism. However, at high doses, BCP produced a reduction in METH self-administration in CB2-KO mice in a manner similar as in WT mice, suggesting that non-CB2 receptor mechanisms underlie high dose BCP-produced effects. In addition, BCP dose-dependently attenuated METH-enhanced electrical BSR and inhibited METH-primed and cue-induced reinstatement of drug-seeking in rats. In vivo microdialysis assays indicated that BCP alone did not produce a significant reduction in extracellular dopamine (DA) in the nucleus accumbens (NAc), while BCP pretreatment significantly reduced METH-induced increases in extracellular NAc DA in a dose-dependent manner, suggesting a DA-dependent mechanism involved in BCP action. Together, the present findings suggest that BCP might be a promising therapeutic candidate for the treatment of METH use disorder.

Highlights

Methamphetamine (METH) is one of the most addictive psychostimulants
Our previous study found that JWH 133, a selective CB2 receptor agonist, dose-dependently inhibits intravenous cocaine self-administration and this effect is blocked by AM630, a selective CB2 receptor antagonist, and is absent in CB2-KO mice (Xi et al, 2011)
We found that systemic administration of the natural CB2R agonist BCP (Gertsch et al, 2008) dosedependently inhibited intravenous METH self-administration, METH-enhanced brain-stimulation reward, and METH- or cue-induced drug-seeking in rats

Summary

INTRODUCTION

Methamphetamine (METH) is one of the most addictive psychostimulants. Following cannabis, it is the second most widely abused illicit drug worldwide–possibly due to its widespread availability and relatively low costs (Brensilver et al, 2013; Panenka et al, 2013; Rawson, 2013). Our previous study found that JWH 133, a selective CB2 receptor agonist, dose-dependently inhibits intravenous cocaine self-administration and this effect is blocked by AM630, a selective CB2 receptor antagonist, and is absent in CB2-KO mice (Xi et al, 2011) These findings suggest that brain CB2 receptors might be a new target in medication development for the treatment of substance use disorders. 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) It is unknown whether BCP is effective against METH reward, intake, and relapse. In the present study, we investigated: 1) whether BCP treatment can inhibit METH self-administration under both fixed-ratio 2 (FR2) and progressive-ratio (PR) schedules of reinforcement in rats; 2) whether deletion of CB2 receptors in CB2-knockout (CB2-KO) mice prevents BCP action on METH self-administration; 3) whether BCP can block METH action on electrical brain-stimulation reward in rats; 4) whether BCP can reduce METH- or cue-induced reinstatement of drug seeking; and 5) whether a dopamine-dependent mechanism is involved in BCP’s potential therapeutic effects against METH-taking and METH-seeking behavior, as assessed by in vivo microdialysis

MATERIALS AND METHODS

General Procedure

RESULTS

DISCUSSION

Findings

ETHICS STATEMENT