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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.
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1 Department of Biology, William Paterson University, Wayne, New Jersey, USA; Laboratory of Clinical Investigation, national Institute on Aging, National Institutes of Health, Baltimore, MD, USA
2 Department of Biology, William Paterson University, Wayne, New Jersey, USA
3 Molecular Targets and medications Discovery Branch, Intramural Research Program. National Institute on Drug Abuse, Baltimore, MD, USA
4 Department of Psychiatry, University of Yamanashi, Yamanashi, Japan
5 Department of Psychiatry, Harvard Medical School, Psychiatric Neurogenomics, Division of Alcohol and Drug Abuse, and Mailman Neuroscience Research Center, McLean Hospital, Belmont, MA, USA
6 Faculty of Medical Science, Santa Casa, Sao Paulo, Brazil
7 Laboratory of Clinical Investigation, national Institute on Aging, National Institutes of Health, Baltimore, MD, USA