Cannabinoid Receptor Type 1 Regulates Drug Reward Behavior via Glutamate Decarboxylase 67 Transcription.

Sun Mi Gu,Daejin Park,Hye Jin Cha,Sowoon Seo,Kyoung-Moon Han,Jin Tae Hong,Sangmin Lee,Jaesuk Yun,Santosh Lamichhane,Sanghyeon Kim,Young-Hoon Kim

doi:10.3390/ijms221910486

Abstract

Interaction of cannabinoid receptor type 1 (CB1) and GABAergic neuronal activity is involved in drug abuse-related behavior. However, its role in drug-dependent Pavlovian conditioning is not well understood. In this study, we aimed to evaluate the effects of a CB1 agonist, JWH-210, on the development of conditioned place preference (CPP)-induced by methamphetamine (METH). Pretreatment with a synthetic cannabinoid, JWH-210 (CB1 agonist), increased METH-induced CPP score and METH-induced dopamine release in acute striatal slices. Interestingly, CB1 was expressed in glutamate decarboxylase 67 (GAD67) positive cells, and overexpression of CB1 increased GAD67 expression, while CB1 knockdown reduced GAD67 expression in vivo and in vitro. GAD67 is known as an enzyme involved in the synthesis of GABA. CB1 knockdown in the mice striatum increased METH-induced CPP. When GAD67 decreased in the mice striatum, mRNA level of CB1 did not change, suggesting that CB1 can regulate GAD67 expression. GAD67 knockdown in the mouse striatum augmented apomorphine (dopamine receptor D2 agonist)–induced climbing behavior and METH-induced CPP score. Moreover, in the human brain, mRNA level of GAD67 was found to be decreased in drug users. Therefore, we suggest that CB1 potentiates METH-induced CPP through inhibitory GABAergic regulation of dopaminergic neuronal activity.

Highlights

Cannabinoids act on the endocannabinoid system primarily through binding cannabinoid receptor type 1 (CB1), to modulate memory, emotions, and pain [1,2,3,4]
Pre-administration of JWH-210 increased conditioned place preference (CPP) score induced by para-chloroamphetamine (PCA), which is a substituted amphetamine (Figure S4B). These results indicate that JWH-210 increases METH-induced Pavlovian conditioning
We examined the effect of JWH-210, a CB1 agonist, on METHinduced reward

Summary

Introduction

Cannabinoids act on the endocannabinoid system primarily through binding cannabinoid receptor type 1 (CB1), to modulate memory, emotions, and pain [1,2,3,4]. In the hotplate test, ∆9 -Tetrahydrocannabinol (∆9 -THC), a representative cannabinoid accounting for the major psychoactive component in marijuana, induced analgesia in CB1+/+ mice, but not in. ∆9 -THC from natural cannabinoids and synthetic cannabinoids have varying effects, which are typically similar to those of marijuana [7,8,9]. Marijuana affects the dopamine system, which is involved in motivation, reward, and recognition [10,11,12]. Synthetic cannabinoids are potent CB1 agonists and exert

Objectives

Methods

Results

Discussion

Conclusion