Antidepressant-like effect of pioglitazone in the forced swimming test in mice: The role of PPAR-gamma receptor and nitric oxide pathway

In this study, the potential antidepressant-like effects of pioglitazone and the possible involvement of peroxisome proliferator-activated receptor gamma (PPAR gamma) and nitric oxide system in antidepressant effects of pioglitazone were determined using forced swimming test (FST) in mice. Method: After assessment of locomotor activity in open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. Pioglitazone was administered orally with doses (5, 10, 20 and 30 mg/kg) 2 and 4 h before FST. To assess the involvement of PPAR gamma in the possible antidepressant effect of pioglitazone, GW9662, a PPAR gamma antagonist (2 mg/kg) was administered before pioglitazone (20 mg/kg). For determination of possible role of nitric oxide pathway in this effect, a non-specific NOS inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.p.), a specific iNOS inhibitor, aminoguanidine (50 mg/kg, i.p.), or a NO precursor, L-arginine (750 mg/kg, i.p.) was co-administered with pioglitazone, either 2 or 4 h before FST. Results: The immobility time significantly decreased after pioglitazone administration (20 and 30 mg/kg). GW-9662 significantly reversed antidepressant effect of pioglitazone administered 2 and 4 h prior to FST. Co-administration of non-effective doses of pioglitazone and L-NAME revealed antidepressant-like effect in FST; while, co-administration of non-effective doses of aminoguanidine and pioglitazone did not affect the immobility time. L-Arginine also reversed the antidepressant-like effect of pioglitazone. Conclusion: The antidepressant-like effect of pioglitazone on mice in the FST is mediated at least in part through PPAR gamma receptors and nitric oxide pathway. (C )2011 Elsevier B.V. All rights reserved.