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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 CB 2 R agonists (JWH133 or five other CB 2 R agonists)significantly reduced VTA DA neuron action potential (AP)firing rate. Under the patch-clamp whole-cell recording model, JWH133 (10 μM)mildly reduced the frequency of miniature 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 μM)enhanced M-type K + currents and this effect was absent in CB 2−/− mice and abolished by co-administration of a selective CB 2 R antagonist (10 μM, AM630). CB 2 R-mediated inhibition in VTA DA neuron firing can be mimicked by M-current opener (10 μM retigabine)and blocked by M-current blocker (30 μM XE991). In addition, enhancement of neuronal cAMP by forskolin (10 μM)reduced M-current and increased DA neuron firing rate. Finally, pharmacological block of synaptic transmission by NBQX (10 μM), D-APV (50 μM)and picrotoxin (100 μM)in VTA slices failed to prevent CB 2 R-mediated inhibition, while intracellular infusion of guanosine 5'-O-2-thiodiphosphate (600 μM, GDP-β-S)through recording electrode to block postsynaptic G-protein function prevented JWH133-induced reduction in AP firing. Interpretation: Our results suggest that CB 2 Rs modulate VTA DA neuron excitability mainly through an intrinsic mechanism, including a CB 2 R-mediated reduction of intracellular cAMP, and in turn enhancement of M-type K + currents. Fund: This research was supported by the Barrow Neuroscience Foundation, the BNI-BMS Seed Fund, and CNSF (81771437).

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