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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.

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