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

Tipepidine increases dopamine level in the nucleus accumbens without methamphetamine-like behavioral sensitization

“…In our current study, the primary site of the action of tipepidine was not uncovered. However, we recently reported electrophysiological data that tipepidine inhibited dopamine D 2 -receptors-mediated GIRK currents in acutely dissociated ventral tegmental area (VTA) dopaminergic neurons [20], and that tipepidine increased double immunopositive cells for tyrosine hydroxylase and c-Fos in the VTA [20]. In this context, it is likely that tipepidine may activate mesolimbic dopaminergic neurons via the direct inhibition of GIRK channels in VTA dopaminergic neurons to facilitate dopamine release in the NAc.…”

“…Single injection of tipepidine(20,40 and 80 mg/kg, i.p.) dosedependently increased extracellular dopamine levels both in the shell and core of the NAc, compared to the pre administration base-line [peak value of dopamine level, Fig.…”

Tipepidine in children with attention deficit/hyperactivity disorder: a 4-week, open-label, preliminary study

“…Very recently, Hamasaki et al showed that tipepidine activated dopamine neurons in the ventral tegmental area through the inhibition of GIRK channel-activated currents, and their preliminary microdialysis study showed that tipepidine dramatically increased dopamine levels in the shell of the nucleus accumbens (NAc) 26. In addition, Costa Dias et al identified the possible involvement of NAc connections in the pathophysiology of impulsive decision making in ADHD, using functional connectivity magnetic resonance imaging 27.…”

Structural Insights into GIRK Channel Function

“…A recent study reported that the antitussive drug, Tipepidine, also blocks GIRK channels (Hamasaki, Shirasaki, Soeda, & Takahama, 2013). Interestingly, this drug appears to have novel antidepressant-like effects that may be mediated through activation of mesolimbic dopamine neurons through GIRK channel inhibition (Hamao et al, 2015;Hamasaki et al, 2013;Kawahara et al, 2013).…”

“…Interestingly, this drug appears to have novel antidepressant-like effects that may be mediated through activation of mesolimbic dopamine neurons through GIRK channel inhibition (Hamao et al, 2015;Hamasaki et al, 2013;Kawahara et al, 2013). Two pilot studies suggest that tipepidine may improve adolescent depression and ADHD (Sasaki, Hashimoto, Tachibana, Kurata, Kimura, et al, 2014;Sasaki, Hashimoto, Tachibana, Kurata, Okawada, et al, 2014).…”