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dc.contributor.authorMa, Zegang
dc.contributor.authorGao, Fenfei
dc.contributor.authorLarsen, Brett
dc.contributor.authorGao, Ming
dc.contributor.authorLuo, Zhihua
dc.contributor.authorChen, Dejie
dc.contributor.authorMa, Xiaokuang
dc.contributor.authorQiu, Shenfeng
dc.contributor.authorZhou, Yu
dc.contributor.authorXie, Junxia
dc.contributor.authorXi, Zheng-Xiong
dc.contributor.authorWu, Jie
dc.date.accessioned2019-08-21T21:40:44Z
dc.date.available2019-08-21T21:40:44Z
dc.date.issued2019-01-03
dc.identifier.citationMa, Z., Gao, F., Larsen, B., Gao, M., Luo, Z., Chen, D., ... & Xi, Z. X. (2019). Mechanisms of cannabinoid CB2 receptor-mediated reduction of dopamine neuronal excitability in mouse ventral tegmental area. EBioMedicine, 42, 225-237.en_US
dc.identifier.issn2352-3964
dc.identifier.pmid30952618
dc.identifier.doi10.1016/j.ebiom.2019.03.040
dc.identifier.urihttp://hdl.handle.net/10150/633914
dc.description.abstractBackground: 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.en_US
dc.description.sponsorshipBarrow Neuroscience Foundation; BNI-BMS Seed Fund; CNSF [81771437]en_US
dc.language.isoenen_US
dc.publisherELSEVIER SCIENCE BVen_US
dc.rightsCopyright © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).en_US
dc.subjectCB2 receptoren_US
dc.subjectCannabinoiden_US
dc.subjectDopamine neuronen_US
dc.subjectVentral tegmental areaen_US
dc.titleMechanisms of cannabinoid CB2 receptor-mediated reduction of dopamine neuronal excitability in mouse ventral tegmental areaen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Coll Med, Dept Basic Med Scien_US
dc.identifier.journalEBIOMEDICINEen_US
dc.description.noteOpen access journalen_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleEBioMedicine
refterms.dateFOA2019-08-21T21:40:45Z


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