► Tipepidine produces an antidepressant like effect in the forced swimming test. ► The effect of tipepidine may be produced via dopamine D 1 and alpha2 adrenoceptor. ► The properties of the effect may be different from those of known antidepressants. We previously reported that the centrally acting non-narcotic antitussive, tipepidine, produces a novel antidepressant-like effect in the forced swimming test in rats, but the mechanism of the antidepressant-like effect of tipepidine is not clear. We investigated the pharmacological mechanism of the antidepressant-like effect of tipepidine in the forced swimming test in rats. A catecholamine-depleting agent, alpha-methyl- p-tyrosine (AMPT; 300 mg/kg, s.c.), was given 6 h before the first injection and with the last injection of tipepidine (40 mg/kg, i.p.). A serotonin (5-HT)-depleting agent, p-chlorophenylalanine (PCPA; 350 mg/kg, i.p.), was given 72 h and 48 h before the pretest session. The dopamine D 1 receptor antagonist, SCH23390 (0.02 mg/kg, s.c.) was given 15 min before each of the three injections of tipepidine. The dopamine D 2 receptor antagonist raclopride (0.2 mg/kg, s.c.), the alpha 1 adrenoceptor antagonist prazosin (1 mg/kg, i.p.), the alpha 2 adrenoceptor antagonist yohimbine (2 mg/kg, i.p.) and the beta adrenoceptor antagonist propranolol (2 mg/kg, i.p.) were given 30 min before each of the three injections of tipepidine. AMPT, but not PCPA, significantly inhibited the immobility time-reducing effect of tipepidine in the forced swimming test. Furthermore, the effect of tipepidine was significantly inhibited by SCH23390 and yohimbine. However, raclopride, prazosin, and propranolol failed to block the effect of tipepidine. The results suggest that the antidepressant-like effect of tipepidine in the forced swimming test may be due at least in part to the effects of dopamine and noradrenaline released at the dopamine D 1 receptor and alpha 2 adrenoceptor, respectively.