title: NMDA receptor involvement in antidepressant-like effect of pioglitazone in the forced swimming test in mice.
abstract: BACKGROUND
  Previously, we showed that pioglitazone exerts its antidepressant-like effect through peroxisome proliferator-activated receptor gamma receptors and demonstrated the possible involvement of calcium-dependent nitric oxide synthase inhibitors. Based upon the in vitro results, pioglitazone reduces N-methyl-D-aspartate (NMDA)-mediated calcium currents in hippocampal neurons.
  
  
  OBJECTIVE
  In this study, we evaluated the involvement of the NMDA receptor (NMDAR) on the antidepressant-like effect of pioglitazone in the forced swimming test (FST) in mice.
  
  
  METHODS
  After the assessment of locomotor activity in the 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 of 5, 10, and 20 mg/kg 4 h before FST. To assess the involvement of NMDARs in the possible antidepressant-like effect of pioglitazone, a selective glutamate receptor agonist, NMDA (75 mg/kg, intraperitoneally [i.p.] or 20 ng/mouse, intracerebroventricularly [i.c.v.]), was administered before pioglitazone (20 mg/kg). To further determine a possible role of NMDARs in this effect, a noncompetitive antagonist of the NMDA, MK-801 (0.05 mg/kg, i.p. or 100 ng/mouse, i.c.v.), was coadministered with pioglitazone (10 mg/kg) 4 h prior to FST.
  
  
  RESULTS
  Pioglitazone (20 mg/kg) administered 4 h prior to FST significantly reduced the immobility time. Coadministration of the noneffective doses of pioglitazone and MK-801 revealed an antidepressant-like effect in FST. Moreover, NMDA significantly reversed the antidepressant-like effect of pioglitazone administered 4 h prior to FST.
  
  
  CONCLUSIONS
  The antidepressant-like effect of pioglitazone in the FST is mediated partly through NMDAR signaling. This study provides a new approach for the treatment of depression.
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Salehi-Sadaghiani
authors.forename: Mehrak
authors.initials: M
authors.lastname: Javadi-Paydar
authors.forename: Mohammad Hadi
authors.initials: MH
authors.lastname: Gharedaghi
authors.forename: Ali
authors.initials: A
authors.lastname: Zandieh
authors.forename: Pouria
authors.initials: P
authors.lastname: Heydarpour
authors.forename: Yashar
authors.initials: Y
authors.lastname: Yousefzadeh-Fard
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects*; D000077205:Pioglitazone; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013550:Swimming; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D016194:Receptors, N-Methyl-D-Aspartate; D045162:Thiazolidinediones; D016291:Dizocilpine Maleate; D000077205:Pioglitazone