NMDA receptor involvement in antidepressant-like effect of pioglitazone in the forced swimming test in mice

• Published in: Psychopharmacologia Vol. 223; no. 3; pp. 345 - 355
• Main Authors: Salehi-Sadaghiani, Mohammad, Javadi-Paydar, Mehrak, Gharedaghi, Mohammad Hadi, Zandieh, Ali, Heydarpour, Pouria, Yousefzadeh-fard, Yashar, Dehpour, Ahmad Reza
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.10.2012; Springer; Springer Nature B.V
• Subjects: Adult and adolescent clinical studies; Animals; Antidepressants; Antidepressive Agents - pharmacology; Aspartate; Behavior, Animal - drug effects; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain; Depression; Depression, Mental; Dizocilpine Maleate - pharmacology; Dose-Response Relationship, Drug; Drug Interactions; Glutamate; Male; Medical sciences; Mental depression; Methyl aspartate; Mice; Mice, Inbred Strains; Mood disorders; Motor Activity - drug effects; Neurons; Neuropharmacology; Neurosciences; Nitric oxide; Original Investigation; Pharmacology. Drug treatments; Pharmacology/Toxicology; Psychiatry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Rodents; Signal transduction; Swimming; Thiazolidinediones - pharmacology; Iran; Forced swimming test; aspartate (NMDA) receptor; Pioglitazone; Depression; methyl; Mice; Thiazolidinedione; PPAR-γ; Mood disorder; Agonist; Psychotropic; Rodentia; Thiazolidinedione derivatives; Glutamate receptor; PPAR-γ receptor; Stress; N-methyl-D-aspartate (NMDA) receptor; Vertebrata; Hypoglycemic agent; Mammalia; Mouse; Animal; NMDA; Antidepressant agent; NMDA receptor
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-012-2722-0

Rationale 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. Method 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. Conclusion 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.