Cannabinoid CB1 Receptors Are Expressed in a Subset of Dopamine Neurons and Underlie Cannabinoid-Induced Aversion, Hypoactivity, and Anxiolytic Effects in Mice.

Cannabinoids modulate dopamine (DA) transmission and DA-related behavior, which has been thought to be mediated by activation of cannabinoid CB1 receptors (CB1Rs) on GABA neurons. However, there is no behavioral evidence supporting it. In contrast, here we report that CB1Rs are expressed in a subset of DA neurons and functionally underlie cannabinoid action in male and female mice. RNAscope ISH assays demonstrated CB1 mRNA in TH-positive DA neurons in the VTA and glutamate decarboxylase 1 (GAD1)-positive GABA neurons. The CB1R-expressing DA neurons were located mainly in the middle portion of the VTA with the density of CB1-TH colocalization progressively decreasing from the medial to the lateral VTA. Triple-staining assays indicated CB1R mRNA colocalization with both TH and vesicular glutamate transporter 2 in the medial VTA close to the midline of the brain. Optogenetic activation of this population of DA neurons was rewarding as assessed by optical intracranial self-stimulation. Δ 9 -tetrahydrocannabinol (Δ 9 -THC) or ACEA (a selective CB1R agonist) dose-dependently inhibited optical intracranial self-stimulation in DAT-Cre control mice, but not in conditional KO mice with the CB1R gene absent in DA neurons. In addition, deletion of CB1Rs from DA neurons attenuated Δ 9 -THC-induced reduction in DA release in the NAc, locomotion, and anxiety. Together, these findings indicate that CB1Rs are expressed in a subset of DA neurons that corelease DA and glutamate, and at least in part functionally underlie cannabinoid modulation of DA release and DA-related behavior. Significance Statement: Cannabinoids produce a series of psychoactive effects, such as aversion and locomotor inhibition in rodents. However, the cellular and receptor mechanisms underlying these actions are not fully understood. Here we report that CB1 receptors are expressed not only in GABA neurons but also in a subset of dopamine neurons, which are located mainly in the medial VTA close to the midline of the midbrain and corelease dopamine and glutamate. Optogenetic activation of these dopamine neurons is rewarding, which is dose-dependently inhibited by cannabinoids. Selective deletion of CB1 receptor from dopamine neurons blocked cannabinoid-induced aversion, hypoactivity, and anxiolytic effects. These findings demonstrate that dopaminergic CB1 receptors also play an important role in mediating cannabinoid action.