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Mechanisms of cannabinoid CB2 receptor-mediated reduction of dopamine neuronal excitability in mouse ventral tegmental areaMa, Zegang; Gao, Fenfei; Larsen, Brett; Gao, Ming; Luo, Zhihua; Chen, Dejie; Ma, Xiaokuang; Qiu, Shenfeng; Zhou, Yu; Xie, Junxia; et al. (ELSEVIER SCIENCE BV, 2019-01-03)Background: We have recently reported that activation of cannabinoid type 2 receptors (CB(2)Rs) reduces dopamine (DA) neuron excitability in mouse ventral tegmental area (VTA). Here, we elucidate the underlying mechanisms. Methods: Patch-clamp recordings were performed in mouse VTA slices and dissociated single VTA DA neurons. Findings: Using cell-attached recording in VTA slices, bath-application of CB2R agonists (JWH133 or five other CB2R agonists) significantly reduced VTA DA neuron action potential (AP) firing rate. Under the patch-clamp whole-cell recordingmodel, JWH133 (10 mu M) mildly reduced the frequency ofminiature excitatory postsynaptic currents (mEPSCs) but not miniature inhibitory postsynaptic currents (mIPSCs). JWH133 also did not alter evoked EPSCs or IPSCs. In freshly dissociated VTA DA neurons, JWH133 reduced AP firing rate, delayed AP initiation and enhanced AP after-hyperpolarization. In voltage-clamp recordings, JWH133 (1 mu M) enhanced M-type K+ currents and this effect was absent in CB -/-mice and abolished by co-administration of a selective CB2R antagonist (10 mu M, AM630). CB2R-mediated inhibition in VTA DA neuron firing can be mimicked by M-current opener (10 mu M retigabine) and blocked by M-current blocker (30 mu M XE991). In addition, enhancement of neuronal cAMP by forskolin (10 mu M) reduced M-current and increased DA neuron firing rate. Finally, pharmacological block of synaptic transmission by NBQX (10 mu M), D-APV (50 mu M) and picrotoxin (100 mu M) in VTA slices failed to prevent CB2R-mediated inhibition, while intracellular infusion of guanosine 5'-O-2-thiodiphosphate (600 mu M, GDP-beta-S) through recording electrode to block postsynaptic G-protein function prevented JWH133-induced reduction in AP firing. Interpretation: Our results suggest that CB2Rs modulate VTA DA neuron excitability mainly through an intrinsic mechanism, including a CB2R-mediated reduction of intracellular cAMP, and in turn enhancement of M-type K+ currents.