title: Tipepidine activates VTA dopamine neuron via inhibiting dopamine D₂ receptor-mediated inward rectifying K⁺ current.
abstract: We previously reported that the novel antidepressant-like effect of tipepidine may be produced at least partly through the activation of mesolimbic dopamine (DA) neurons via inhibiting G protein-coupled inwardly rectifying potassium (GIRK) channels. In this study, we investigated the action of tipepidine on DA D2 receptor-mediated GIRK currents (IDA(GIRK)) and membrane excitability in DA neurons using the voltage clamp and current clamp modes of the patch-clamp techniques, respectively. DA neurons were acutely dissociated from the ventral tegmental area (VTA) in rats and identified by the presence of the hyperpolarization-activated currents. Tipepidine reversibly inhibited IDA(GIRK) with IC50 7.0 μM and also abolished IDA(GIRK) irreversibly activated in the presence of intracellular GTPγS. Then tipepidine depolarized membrane potential and generated action potentials in the neurons current-clamped. Furthermore, the drug at 40 mg/kg, i.p. increased the number of cells immunopositive both for c-Fos and tyrosine hydroxylase (TH) in the VTA. These results suggest that tipepidine may activate DA neurons in VTA through the inhibition of GIRK channel-activated currents.
authors.affiliation: Department of Environmental and Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Hamasaki
authors.forename: T
authors.initials: T
authors.lastname: Shirasaki
authors.forename: F
authors.initials: F
authors.lastname: Soeda
authors.forename: K
authors.initials: K
authors.lastname: Takahama
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D010880:Piperidines; D017448:Receptors, Dopamine D2; C028458:tipepidine
keywords: 5-HT; DA; G protein-coupled inwardly rectifying potassium channel; G-protein-coupled inwardly rectifying potassium; G-protein-coupled receptor; GIRK; GPCR; I(Baclofen); I(DA(GIRK)); I(DA); I(h); IPSCs; NA; NAT; NAc; OCD; PB; S.E.M.; SERT; SNc; TBS; TBST; TH; TritonX-100 in TBS; VTA; acutely dissociated neuron; baclofen-induced current; dopamine; dopamine D(2) receptor-mediated GIRK current; dopamine-induced current; hyperpolarization-activated cation current; inhibitory postsynaptic currents; noradrenaline; noradrenaline transporter; nucleus accumbens; obsessive–compulsive disorder; patch clamp; phosphate buffer; serotonin; serotonin transporter; standard error of the mean; substantia nigra pars compacta; tipepidine; tris-buffered saline; tyrosine hydroxylase; ventral tegmental area