Effects of ifenprodil on the antidepressant-like activity of NMDA ligands in the forced swim test in mice

Abstract

Multiple pre-clinical and clinical studies clearly displayed implication of the NMDA receptors in development of depressive disorders since a variety of NMDA receptor antagonists exhibit an antidepressant-like effect. The main aim of our study was to assess the influence of ifenprodil - an allosteric modulator selectively binding at the NR2B subunit on the performance in the forced swim test in mice of various NMDA receptor ligands interacting with distinct components of the NMDA receptor complex. Ifenprodil at a dose of 10mg/kg enhanced the antidepressant-like effect of CGP 37849 (a competitive NMDA receptor antagonist, 0.312mg/kg), L-701,324 (an antagonist at glycine site, 1mg/kg), MK-801 (a non-competitive antagonist, 0.05mg/kg) and d-cycloserine (a partial agonist of a glycine site, 2.5mg/kg) but it did not shorten the immobility time of animals which concurrently received an inorganic modulator of the NMDA receptor complex, such as Zn(2+) (2.5mg/kg) or Mg(2+) (10mg/kg). On the other hand, the antidepressant-like effect of ifenprodil (20mg/kg) was reversed by N-methyl-d-aspartic acid (an agonist at the glutamate site, 75mg/kg) or d-serine (an agonist at the glycine site, 100nmol/mouse). In conclusion, the antidepressant-like potential of ifenprodil given concomitantly with NMDA ligands was either reinforced (in the case of both partial agonist and antagonists, except for magnesium and zinc) or diminished (in the case of conventional full agonists).

Keywords: 7-chloro-4-hydroxy-3-(3-phenoxy)phenylquinolin-2[1H]-one; Antidepressant-like activity; CGP 37849; DCS; DS; FST; Forced swim test; Ifenprodil; L-701,324; MK-801; Mice; N-methyl-d-aspartate; NMDA; NMDA receptor ligands; TST; d-cycloserine (d-4-amino-3-isoxazolidone); d-serine; dizocilpine ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate); dl-/E/-amino-4-methyl-5-phosphono-3-pentenoic acid; forced swim test; i.c.v; i.p; intracerebroventricularly; intraperitoneally; tail suspension test.