Blockade of TRPV1 Inhibits Methamphetamine-induced Rewarding Effects

Yu-Hua Tian,George F Koob,Kwang-Wook Lee,Choon-Gon Jang,Shi-Xun Ma,Seok-Yong Lee,Sunmee Wee

doi:10.1038/s41598-018-19207-2

Abstract

Methamphetamine (MAP) is the most widely used psychostimulant in the world, but the exact mechanisms underlying MAP addiction are not yet fully understood. Recent studies have identified the distribution of TRPV1 in several brain regions that are related to drug addiction, including nucleus accumbens (NAc) and dorsal striatum (DSt). In the present study, we performed conditioned place preference (CPP) and self-administration tests to examine the effects of capsazepine (CPZ) and SB366791 (SB) on MAP reward. We found that both CPZ and SB significantly inhibited MAP-induced CPP and self-administration; in contrast, TRPV1 knock-out (KO) mice did not develop MAP-induced CPP. Real-time RT-PCR, Western blot and quantitative autoradiographic tests showed up-regulation of TRPV1 mRNA and protein expression in the NAc and/or DSt regions of mice exhibiting MAP-induced CPP. In addition, an in vivo microdialysis experiment showed that CPZ dramatically reduced dopamine (DA) levels in the NAc region of MAP-treated mice. Furthermore, attenuated dopamine transporter (DAT) binding levels in the NAc and DSt regions of MAP-induced CPP mice were reversed by CPZ. Together, these data suggest that TRPV1 plays an important role in MAP reward via the modulation of DA release and DAT density, thereby providing a novel therapeutic target for MAP addiction.

Highlights

MAP is a psychostimulant and one of the most problematic addictive drugs in the world[15]
We found that levels of TRPV1 mRNA were significantly higher in nucleus accumbens (NAc) region (P < 0.05), but not in the dorsal striatum (DSt) region (P > 0.05), after both conditioned place preference (CPP) development [drug, F(1,35) = 6.456, P > 0.05; region, F(1,35) = 1.731, P < 0.05; drug × region interactions, F(1,35) = 1.827, P > 0.05; two-way ANOVA] and the reinstatement test [drug, F(1,35) = 1.514, P > 0.05; region, F(1,35) = 4.404, P < 0.05; drug × region interactions, F(1,35) = 4.393, P < 0.05; two-way ANOVA] (Fig. 4B)
We performed CPP and self-administration tests to examine the effects of CPZ and SB, two competitive TRPV1 antagonists, on MAP reward

Summary

Introduction

MAP is a psychostimulant and one of the most problematic addictive drugs in the world[15]. A growing number of studies have identified the importance of other neurotransmitters and related receptors, including glutamate, GABA, 5-HT, acetylcholine, and endocannabinoids, in the reward effect of MAP. One study reported that anandamide, an endogenous cannabinoid receptor ligand, was involved in MAP drug-seeking behavior[17]. Activates this channel with a potency and efficacy that are lower than those exhibited at CB1 receptors[2]. Both findings indicate the possible engagement of TRPV1 in MAP abuse. We studied possible mechanisms to explain how TRPV1 may contribute to MAP reward

Methods

Results

Conclusion