期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：46
页码：E5007-E5015
DOI：10.1073/pnas.1413210111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAlthough early studies suggested that cannabinoid CB2 receptors (CB2Rs) are absent in the brain, this view has been challenged by recent findings of significant brain CB2R involvement in several dopamine (DA)-related CNS disorders. The cellular mechanisms underlying these actions are unclear, however. Using multiple approaches, we found that CB2R genes and receptors are expressed in midbrain DA neurons, and that activation of CB2Rs inhibits DA neuronal firing and i.v. cocaine self-administration. These findings not only challenge the long-held view that brain CB2Rs are not expressed in neurons, but also suggest that neuronal CB2Rs modulate DA neuronal activity and DA-regulated behavior. Thus, brain CB2Rs may constitute a new therapeutic target in medication development for treatment of a number of CNS disorders. Cannabinoid CB2 receptors (CB2Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we report that CB2Rs are expressed in ventral tegmental area (VTA) DA neurons and functionally modulate DA neuronal excitability and DA-related behavior. In situ hybridization and immunohistochemical assays detected CB2 mRNA and CB2R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB2Rs by JWH133 or other CB2R agonists inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of JWH133 into the VTA inhibited cocaine self-administration. Importantly, all of the above findings observed in WT or CB1-/- mice are blocked by CB2R antagonist and absent in CB2-/- mice. These data suggest that CB2R-mediated reduction of VTA DA neuronal activity may underlie JWH133's modulation of DA-regulated behaviors.
