Effects of ifenprodil on the antidepressant-like activity of NMDA ligands in the forced swim test in mice Ewa Poleszak a, ⁎, Sylwia Wośko a , Anna Serefko a , Aleksandra Szopa a , Aleksandra Wlaź b , Bernadeta Szewczyk c , Gabriel Nowak c,d , Piotr Wlaź e a Department of Applied Pharmacy, Medical University of Lublin, Chodźki 1, PL 20-093 Lublin, Poland b Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland c Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland d Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland e Department of Animal Physiology, Institute of Biology and Biochemistry, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, PL 20-033 Lublin, Poland abstract article info Article history: Received 23 February 2013 Received in revised form 30 April 2013 Accepted 4 June 2013 Available online 14 June 2013 Keywords: Antidepressant-like activity Forced swim test Ifenprodil Mice NMDA receptor ligands 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 10 mg/kg enhanced the antidepressant-like effect of CGP 37849 (a competitive NMDA receptor antagonist, 0.312 mg/kg), L-701,324 (an antagonist at glycine site, 1 mg/kg), MK-801 (a non-competitive antagonist, 0.05 mg/kg) and D-cycloserine (a partial agonist of a glycine site, 2.5 mg/kg) but it did not shorten the immobility time of animals which con- currently received an inorganic modulator of the NMDA receptor complex, such as Zn 2+ (2.5 mg/kg) or Mg 2+ (10 mg/kg). On the other hand, the antidepressant-like effect of ifenprodil (20 mg/kg) was reversed by N-methyl-D-aspartic acid (an agonist at the glutamate site, 75 mg/kg) or D-serine (an agonist at the glycine site, 100 nmol/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). © 2013 Elsevier Inc. All rights reserved. 1. Introduction Depression is one of the most common recurring psychiatric dis- eases widespread all over the world, which prevalence is still increas- ing. Development of depressive disorders is preliminarily associated with disturbances in noradrenergic and serotonergic transmission in brain (Willner et al., 2012). However, multiple pre-clinical and clinical studies clearly displayed implication of the ionotropic NMDA receptors, as well. Alterations of the glutamate levels and NMDA receptor abnor- malities were observed in depressive patients participating in clinical trials (Hashimoto, 2009; Law and Deakin, 2001; Nowak et al., 2003; Sanacora et al., 2004). Moreover, the involvement of the NMDA neurotransmission in the antidepressant-like effects of paroxetine and tianeptine has been reported (Ghasemi et al., 2009; Wlaź et al., 2011). Similar interactions between the NMDA receptor ligands and imipra- mine, fluoxetine and reboxetine were noticed by Poleszak et al. (2011). The NMDA receptor heteromeric complex is considered as a tetramer comprising two glycine-binding NR1 subunits with two glutamate- binding NR2 subunits or, less frequently two glycine-binding NR3 sub- units. NR1 subunit, ubiquitously distributed in central nervous system, is encoded by a single gene but occurs as eight distinct isoforms. NR2 subunits (NR2A, NR2B, NR2C and NR2D) are encoded by four different genes. Their distribution in the central nervous system is not uniform — NR2A subunits are commonly found in the brain whereas NR2B expression is restricted primarily to the forebrain; NR2C subunits are predominantly localised in the cerebellum. The type of NR2 subunit is thought to determine functional and pharmacological properties of the whole NMDA receptor complex (Bhatt et al., 2013; Traynelis et al., 2010; Williams, 2009). There are numerous binding sites within the NMDA receptor complex, i.e. a binding site for glycine or D-serine, a glutamic acid binding site, the binding sites for zinc, magnesium, poly- amines, redox agents and others (Monaghan and Jane, 2009). Progress in Neuro-Psychopharmacology & Biological Psychiatry 46 (2013) 29–35 Abbreviations: CGP 37849, DL-/E/-amino-4-methyl-5-phosphono-3-pentenoic acid; DCS, D-cycloserine (D-4-amino-3-isoxazolidone); DS, D-serine; FST, forced swim test; i.c.v, intracerebroventricularly; i.p, intraperitoneally; L-701,324, 7-chloro-4-hydroxy- 3-(3-phenoxy)phenylquinolin-2[1H]-one; MK-801, dizocilpine ((5R,10S)-(+)-5-methyl- 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate); NMDA, N-methyl-D-aspartate; TST, tail suspension test. ⁎ Corresponding author. Tel.: +48 81 742 38 08. E-mail address: ewa.poleszak@umlub.pl (E. Poleszak). 0278-5846/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pnpbp.2013.06.001 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp