Cannabinoid CB₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Cannabinoid CB ₂ receptors (CB ₂Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we report that CB ₂Rs 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 CB ₂ mRNA and CB ₂R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB ₂Rs by JWH133 or other CB ₂R 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 CB ₁⁻/⁻ mice are blocked by CB ₂R antagonist and absent in CB ₂⁻/⁻ mice. These data suggest that CB ₂R-mediated reduction of VTA DA neuronal activity may underlie JWH133's modulation of DA-regulated behaviors. Significance Although early studies suggested that cannabinoid CB ₂ receptors (CB ₂Rs) are absent in the brain, this view has been challenged by recent findings of significant brain CB ₂R involvement in several dopamine (DA)-related CNS disorders. The cellular mechanisms underlying these actions are unclear, however. Using multiple approaches, we found that CB ₂R genes and receptors are expressed in midbrain DA neurons, and that activation of CB ₂Rs inhibits DA neuronal firing and i.v. cocaine self-administration. These findings not only challenge the long-held view that brain CB ₂Rs are not expressed in neurons, but also suggest that neuronal CB ₂Rs modulate DA neuronal activity and DA-regulated behavior. Thus, brain CB ₂Rs may constitute a new therapeutic target in medication development for treatment of a number of CNS disorders.