Depression is a common illness with severe morbidity and mortality. Nitric oxide synthase (NOS) inhibitors are shown to elicit antidepressant-like effect in various animals models. It is widely known that serotonin plays an important role in the antidepressant-like effect of drugs. The aim of this study is to investigate the involvement of 5-HT1 and 5-HT2 receptor subtypes in the antidepressant-like effect of TRIM, a nNOS inhibitor, in the rat forced swimming test (FST). TRIM displays an antidepressant-like activity in FST which is blocked by pretreatment with the NOS substrate L-arginine. Depletion of endogenous serotonin using para-chlorophenylalanine (pCPA: 3 x 150 mg/kg, i.p.) partially attenuated TRIM (50 mg/kg)-induced reductions in immobility time in FST. Pretreatment with methiothepin (0.1 mg/kg, i.p, a non-selective 5-HT receptor antagonist), cyproheptadine (3 mg/kg i.p, a 5-HT2 receptor antagonist) or ketanserin (5 mg/kg i.p, a 5HT(2A/2c) receptor antagonist) prevented the effect of TRIM (50 mg/kg) in the FST. WAY 100635 (0.1 mg/kg i.p, a selective 5-HT, A receptor antagonist) and GR 127935 (3 mg/kg i.p, a selective 5-HT1B/1D receptor antagonist) slightly reversed the immobility-reducing effect of TRIM in the FST, but this failed to reach a statistically significant level. The results of this study demonstrate that antidepressant-like effect of TRIM in the FST seems to be mediated, at least in part, by an interaction with 5-HT2 receptors while non-significant effects were obtained with 5-HT1 receptors. (C) 2010 Elsevier Inc. All rights reserved.