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

Xiao Han, Ying Liang, Briana J. Hempel, Chloe J. Jordan, Hui Shen, Guo-Hua Bi, Jin Li, Zheng-Xiong Xi

Journal of Neuroscience January 18, 2023 DOI: 10.1523/jneurosci.1493-22.2022 (opens in new tab)

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AI-extracted from the abstract
Characteristics Preclinical experimental study Peer reviewed
Population Male and female mice
Interventions Δ9-tetrahydrocannabinol (Δ9-THC) ACEA optogenetic activation
Measures optical intracranial self-stimulation, RNAscope in situ hybridization
Topics Anxiety
Keywords 9-tetrahydrocannabinol Cb1 receptor Aversion Cannabinoid Dopamine neurons Locomotion
Key findings CB1 receptors are expressed on a subset of VTA dopamine neurons that co-release dopamine and glutamate, and these receptors functionally mediate cannabinoid modulation of dopamine release and dopamine-related behaviors. Δ9-THC and ACEA dose-dependently inhibited optical intracranial self-stimulation in control mice but not in mice with CB1R deleted from dopamine neurons, and this deletion attenuated Δ9-THC-induced reductions in nucleus accumbens dopamine release, locomotion, and anxiety.

Abstract

Cannabinoids modulate dopamine (DA) transmission and DA-related behavior, which has been thought to be mediated initially 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 also expressed in a subset of DA neurons and functionally underlie cannabinoid action in male and female mice. RNAscope in situ hybridization (ISH) assays demonstrated CB1 mRNA in tyrosine hydroxylase (TH)-positive DA neurons in the ventral tegmental area (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 number 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 (VgluT2, a glutamate neuronal marker) 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. Δ9-tetrahydrocannabinol (Δ9-THC) or ACEA (a selective CB1R agonist) dose-dependently inhibited optical intracranial self-stimulation in DAT-Cre control mice, but not in conditional knockout mice with the CB1R gene absent in DA neurons. In addition, deletion of CB1Rs from DA neurons attenuated Δ9-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 functionally underlie cannabinoid modulation of DA release and DA-related behavior.SIGNIFICANCE STATEMENT Cannabinoids produce a series of psychoactive effects, such as aversion, anxiety, 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 play an important role in mediating cannabinoid action.

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