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

We previously reported that the novel antidepressant-like effect of tipepidine may be produced at least partly through the activation of mesolimbic dopamine neurons via inhibition of G protein-coupled inwardly rectifying potassium channels. In this study, we investigated whether tipepidine increases dopamine levels in the nucleus accumbens (NAc) in rats using an in vivo microdialysis technique. We further assessed whether tipepidine at antidepressant-like effective doses induces behavioral- and cross-sensitization of locomotor activity in rats using the open field test. We found that acute administration of tipepidine increased dopamine levels in the NAc in freely moving rats without increasing locomotor activity. Tipepidine at antidepressant-like effective doses (20 and 40 mg/kg, i.p.) did not cause behavioral sensitization in rats. Furthermore, cross-sensitization between tipepidine and methamphetamine was not observed in rats. These results further support our working hypothesis that tipepidine may produce a novel antidepressant-like effect through activation of ventral tegmental area-NAc dopaminergic neurons whose mechanisms differ from those contributing to the reinforcing effects of addictive drugs.