The use of lithium in combination with various antidepressant drugs (e.g., heterocyclics and monoamine oxidase inhibitors) has been reported rapidly to improve antidepressant response in otherwise treatment-resistant patients. Carbamazepine and sodium valproate have also been shown to be effective in the treatment of several forms of affective disorders, such as treatment-resistant depression and bipolar depression. The present study, using the mouse forced swimming test, was undertaken to test the hypothesis of the action of lithium, carbamazepine or sodium valproate on some 5-HT receptor subtypes. Results showed that lithium significantly potentiated the anti-immobility effects of RU 24969 (P<0.01) and anpirtoline (P<0.01). Pretreatment with lithium did not induce any significant antidepressant-like effects when tested in combination with 8-OH-DPAT, NAN-190 or (+/-) pindolol. Pretreatment with carbamazepine provoked anti-immobility effects when tested in combination with RU 24969 (P<0.01) and 8-OH-DPAT (P<0.01), whereas prior administration of sodium valproate enhanced the antidepressant-like effects of (+/-) pindolol (P<0.01), 8-OH-DPAT (P<0.01) and RU 24969 (P<0.01). In conclusion, the results of the present study suggest that lithium may be acting through 5-HT1B receptors, whereas the action of carbamazepine and sodium valproate seems to involve 5-HT1A receptors in the mouse forced swimming test. However, considering the complexity of the actions of these compounds, it is possible that other neurotransmitter systems/receptors may be involved.