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 (PPARγ) 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 PPARγ in the possible antidepressant effect of pioglitazone, GW9662, a PPARγ 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, Nω-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 PPARγ receptors and nitric oxide pathway.