Cannabinoid CB1 receptors are expressed in a subset of dopamine neurons and underlie cannabinoid modulation of DA release and DA-related behavior in mice
作者机构：Beijing Key Laboratory of NeuropsychopharmacologyState Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology Addiction Biology Unit Molecular Targets and Medications Discovery Branch Intramural Research Program National Institute on Drug Abuse
出 版 物：《中国药理学与毒理学杂志》 (Chinese Journal of Pharmacology and Toxicology)
年 卷 期：2023年第37卷第7期
页 面：535-536页
学科分类：1006[医学-中西医结合] 10[医学] 100602[医学-中西医结合临床]
摘 要：OBJECTIVE 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, the cellular and receptor mechanisms underlying cannabinoids′ psychoactive effects are not fully understood. The present study is to explore the possible expression character of CB1Rs and elucidated the underlying mechanism of them. METHODS We took advantage of RNAscope in situ hybridization(ISH)assays and triple-staining assays to detect the CB1Rexpressing neurons. We established an optical intracranial self-stimulation(OICSS) behavioral model by using optogenetics to study dopaminergic reinforcement function.Natural and synthetic cannabinoids were used to study the function of CB1Rs. Conditional genetic depletion of CB1Rs and behavioral assay were performed to study the modulatory role of CB1Rs in DA-related behaviors.RESULTS We found that CB1Rs are also expressed in a subset of DA neurons and functionally underlie cannabinoid action in male and female mice. 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 OICSS.D9-tetrahydrocannabinol(D9-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 D9-THC-induced reduction in DA release in the NAc, locomotion, and anxiety. CONCLUSION Our results indicated 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.
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