Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference

Qing-Rong Liu,Josephine M Egan,Jeung Woon Lee,Joao Carlos Escosteguy-Neto,Eliot L Gardner,Hiroki Ishiguro,Zheng-Xiong Xi,Norman Schanz,Branden Sanabria,Zhicheng Lin,Claire M Leonard,Eugene Dennis,Emmanuel S Onaivi,Jair Guilherme Santos-Junior,Susan Sgro,Hai-Ying Zhang,Patricia Tagliaferro,Monika Chung,Ana Canseco-Alba

doi:10.1038/s41598-017-17796-y

Abstract

Cannabinoid CB2 receptors (CB2Rs) are expressed in mouse brain dopamine (DA) neurons and are involved in several DA-related disorders. However, the cell type-specific mechanisms are unclear since the CB2R gene knockout mice are constitutive gene knockout. Therefore, we generated Cnr2-floxed mice that were crossed with DAT-Cre mice, in which Cre- recombinase expression is under dopamine transporter gene (DAT) promoter control to ablate Cnr2 gene in midbrain DA neurons of DAT-Cnr2 conditional knockout (cKO) mice. Using a novel sensitive RNAscope in situ hybridization, we detected CB2R mRNA expression in VTA DA neurons in wildtype and DAT-Cnr2 cKO heterozygous but not in the homozygous DAT-Cnr2 cKO mice. Here we report that the deletion of CB2Rs in dopamine neurons enhances motor activities, modulates anxiety and depression-like behaviors and reduces the rewarding properties of alcohol. Our data reveals that CB2Rs are involved in the tetrad assay induced by cannabinoids which had been associated with CB1R agonism. GWAS studies indicates that the CNR2 gene is associated with Parkinson’s disease and substance use disorders. These results suggest that CB2Rs in dopaminergic neurons may play important roles in the modulation of psychomotor behaviors, anxiety, depression, and pain sensation and in the rewarding effects of alcohol and cocaine.

Highlights

Cannabinoid CB2 receptors (CB2Rs) are expressed in mouse brain dopamine (DA) neurons and are involved in several DA-related disorders
In this study we examined the effect of specific deletion of CB2Rs in DA neurons in dopamine transporter gene (DAT)-Cnr[2] conditional knockout (cKO) mice
The CB2R floxed mice were crossed with DAT-Cre mice, in which the Cre recombinase expression is under dopamine transporter (DAT) gene promoter control to generate conditional dopaminergic DAT-Cnr[2] cKO mice

Summary

Introduction

Cannabinoid CB2 receptors (CB2Rs) are expressed in mouse brain dopamine (DA) neurons and are involved in several DA-related disorders. Wild type and DAT-Cnr[2] cKO mice were sequentially evaluated in the four tests by measuring locomotor activity, rectal temperature, catalepsy, and anti-nociception after the administration of vehicle or the selected doses of the cannabinoids.

Results

Conclusion