The present study was undertaken to identify the receptor subtypes involved in (+/-) pindolol's ability to enhance the effects of antidepressant drugs in the mouse forced swimming test. Interaction studies were performed with S 15535 (presynaptic 5-HT1A receptor agonist) and methiothepin (5-HT1B autoreceptor antagonist) in an attempt to attenuate or potentiate antidepressant-like activity. (+/-) Pindolol was tested in combination with selective agonists and antagonists at 5-HT1, 5-HT2 and 5-HT3 receptor subtypes. Pretreatment with S 15535 and methiothepin attenuated the activity of paroxetine, fluvoxamine and citalopram (32 mg/kg, i.p.; P < 0.01). (+/-) Pindolol (32 mg/kg, i.p.) induced significant anti-immobility effects when tested in combination with 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU 24969) (1 mg/kg, i.p.; P < 0.05), 1-(2-methoxyphenyl)-4-[-(2-phthalimido) butyl]piperazine) (NAN 190) (0.5 mg/kg; P < 0.05) and ondansetron (0.00001 mg/kg, i.p.; P < 0.01). Pretreatment with NAN 190 (0.5 mg/kg, i.p.) potentiated the effects of RU 24969 (1 mg/kg, i.p.; P < 0.05) and (+/-) pindolol (32 mg/kg, i.p.; P < 0.05) in the forced swimming test, as did ondansetron (0.00001 mg/kg, i.p.). Significant additive effects were induced when RU 24969 (1 mg/kg, i.p.) was tested in combination with NAN 190 (0.5 mg/kg, i.p.; P < 0.05), (+/-) pindolol (32 mg/kg, i.p.; P < 0.05) and ondansetron (0.0000 mg/kg, i.p.; P < 0.05). 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1 mg/kg, i.p.) or ketanserin (8 mg/kg, i.p.) did not induce significant antidepressant-like effects with any of the agonists/antagonists tested. The results of the present study suggest that pindolol is acting at presynaptic 5-HT1B serotonergic receptors, in addition to the 5-HT1A subtype, in augmenting the activity of antidepressants in the mouse forced swimming test.