The effect of ipsapirone (3 and 10 mg/kg once daily, i.p. for 21 days), was assessed in two animal models of depression, namely the forced swim test and on the hyperactive response of the olfactory bulbectomized (OB) rat in the 'open field' test. The response to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.15 mg/kg, s.c.)-induced hypothermia in rats was examined on day 16 of ipsapirone treatment. In the forced swim test, subacute treatment with ipsapirone (3 and 10 mg/kg) significantly reduced the immobility time in both sham and OB groups. In the OB rat model, chronic treatment with 10 mg/kg ipsapirone antagonized the lesion-induced hyperactivity in the 'open field' apparatus. The hypothermic response to 8-OH-DPAT was attenuated after chronic treatment with 3 mg/kg ipsapirone in both sham and OB groups, while 10 mg/kg ipsapirone attenuated this temperature reduction only in the sham group (p < 0.05). Ipsapirone (10 mg/kg) significantly increased home cage locomotor activity counts on days 15 and 21 of drug treatment in the OB dose group, but only on day 21 in the sham dose group (p < 0.05). Ipsapirone (10 mg/kg) caused a significant reduction in rectal temperature 30 min following drug administration in the sham group on day 1 (p < 0.05) but in the OB group on days 1, 7, 15 and 22 (p < 0.05) of drug treatment. No significant differences in basal serum corticosterone concentrations were found either associated with olfactory bulbectomy or drug treatment. Chronic ipsapirone treatment did not attenuate the reductions in noradrenaline and serotonin in the frontal cortex of OB animals. It can be concluded that ipsapirone shows antidepressant-like activity in the forced swim test and the OB rat model of depression.