Tipepidine activates VTA dopamine neuron via inhibiting dopamine D₂ receptor-mediated inward rectifying K⁺ current

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.