Mechanisms of cannabinoid CB 2 receptor-mediated reduction of dopamine neuronal excitability in mouse ventral tegmental area

Zegang Ma, Fenfei Gao, Brett Larsen, Ming Gao, Zhihua Luo, Dejie Chen, Xiaokuang Ma, Shenfeng Qiu, Yu Zhou, Junxia Xie, Zheng Xiong Xi, Jie Wu

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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).

Original languageEnglish (US)
Pages (from-to)225-237
Number of pages13
JournalEBioMedicine
Volume42
DOIs
StatePublished - Apr 2019

Keywords

  • CB2 receptor
  • Cannabinoid
  • Dopamine neuron
  • Ventral tegmental area

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Mechanisms of cannabinoid CB <sub>2</sub> receptor-mediated reduction of dopamine neuronal excitability in mouse ventral tegmental area'. Together they form a unique fingerprint.

  • Cite this