NMDA receptor/nitrergic system blockage augments antidepressant-like effects of paroxetine in the mouse forced swimming test.
OBJECTIVE
In this study, we evaluated the involvement of N-methyl-D-aspartate receptor (NMDAR)/nitric oxide (NO) system on the antidepressant-like effects of paroxetine in the mouse forced swimming test.


METHODS
Swim sessions were conducted by placing mice in individual glass cylinders filled with water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated.


RESULTS
Paroxetine (8 and 16 mg/kg, intraperitoneal [i.p.]) significantly reduced the immobility times of mice, whereas lower doses (2 and 4 mg/kg) had no effect. NMDA antagonists MK-801 (0.1 and 0.25 mg/kg, i.p.) and ifenprodil (1 and 3 mg/kg, i.p.) and the NO synthase inhibitor NG-L-arginine methyl ester (L-NAME; 30 and 100 mg/kg, i.p.) significantly decreased the immobility time. Lower doses of MK-801 (0.01 and 0.05 mg/kg), ifenprodil (0.1 and 0.5 mg/kg), and L-NAME (10 mg/kg) had no effect. Combined treatment of subeffective doses of paroxetine (4 mg/kg) and MK-801 (0.05 mg/kg), ifenprodil (0.5 mg/kg), and L-NAME (10 mg/kg) robustly exerted an antidepressant-like effect. The noneffective dose of a NO precursor L: -arginine (750 mg/kg, i.p.) prevented the antidepressant-like effect of paroxetine (30 mg/kg).


CONCLUSIONS
We suggested, for the first time, a possible role for NMDAR/NO signaling in the antidepressant-like effects of paroxetine, providing a new approach for the treatment of depression.
Ghasemi
Mehdi
M
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box, 13145-784, Tehran, Iran. m82_ghasemi@yahoo.com
Montaser-Kouhsari
Laleh
L
Shafaroodi
Hamed
H
Nezami
Behtash Ghazi
BG
Ebrahimi
Farzad
F
Dehpour
Ahmad Reza
AR
D000704:Analysis of Variance; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017374:Paroxetine / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013550:Swimming
D018687:Antidepressive Agents, Second-Generation; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D017374:Paroxetine; D016291:Dizocilpine Maleate; C010739:ifenprodil; D019331:NG-Nitroarginine Methyl Ester