We have previously found that antitussive drugs inhibit G protein-coupled inwardly rectifying potassium (GIRK) channel currents in brain neurons. Potassium efflux through GIRK channels causes membrane hyperpolarization, and thus plays an important role in the inhibitory regulation of neuronal excitability. Because GIRK channels are coupled to various G protein-coupled receptors including monoamine receptors, antitussives are possible to affect the levels of various neurotransmitters in the brain. Many currently available antidepressants have been developed based on the monoamine theory for the etiology of depression. We hypothesized that new drugs such as tipepidine may lead to changes in the balance of monoamine levels in the brain resulting in improvement in symptoms of depression. Therefore, we investigated whether or not the drugs have antidepressant activity in the animal models. Male Wistar rats (200-240 g) were used. Tipepidine, cloperastine and caramiphen significantly reduced the immobility in forced swimming test (FST) using normal rats. All drugs had little effect on loco-motor activity. The effects on the forced swimming were inhibited by treatment with AMPT, but not PCPA. Tipepidine also inhibited hyperactivity in olfactory bulbectomized rats. Interestingly, tipepidine also significantly reduced the immobility in FST using ACTH-treated rats which is a model of depression resistant to treatment with antidepressants. Given these results together with cumulated findings, it is suggested that tipepidine may have a novel antidepressant-like action, and that the effect may be caused at least partly through the action on the catecholaminergic system in the brain.