Metabotropic Glutamate 5 Receptor Antagonism Is Associated with Antidepressant-Like Effects in Mice

Abstract

Antidepressant-like effects of metabotropic glutamate (mGlu)5 receptor antagonists have been reported previously. We now provide definitive identification of mGlu5 receptors as a target for these effects through the combined use of selective antagonists and mice with targeted deletion of the mGlu5 protein. In these experiments, the mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and the more selective and metabolically stable analog 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) decreased immobility in the mouse forced swim test, a test predictive of antidepressant efficacy in humans. mGlu5 receptor knockout mice had a phenotype in the forced swim test that was congruent with the effects of receptor blockade; mGlu5 receptor knockout mice were significantly less immobile than their wild-type counterparts. Consistent with mGlu5 receptor mediation of the antidepressant-like effects of MPEP, the effects of MPEP were not observed in mGlu5 receptor knockout mice, whereas comparable effects of the tricyclic antidepressant imiprimine remained active in the mutant mice. MPEP and imiprimine resulted in a synergistic antidepressant-like effect in the forced swim test. The drug interaction was not likely because of increased levels of drugs in the brain, suggesting a pharmacodynamic interaction of mGlu5 and monoaminergic systems in this effect. Thus, the present findings substantiate the hypothesis that mGlu5 receptor antagonism is associated with antidepressant-like effects. This mechanism may not only provide a novel approach to the therapeutic management of depressive disorders but also may be useful in the augmentation of effects of traditional antidepressant agents.Monoamine-based antidepressants have been the primary pharmacological approach to the treatment of mood disorders, but these agents suffer from some limitations in both safety and efficacy that have prompted the continued search for novel therapeutic targets beyond the monoamine system (cf., Skolnick et al., 2001). Glutamate, the major excitatory neurotransmitter used by the mammalian brain, binds to both ion channel-associated (iontropic) and G protein-coupled (metabotropic) receptor subtypes. The glutamatergic system plays a critical role in the pathophysiology of depression and in the action of antidepressant drugs (Skolnick et al., 2001;Kugaya and Sanacora, 2005;Alt et al., 2006). Modulation of ionotropic (e.g., AMPA receptors and NMDA receptors) and metabotropic glutamate (mGlu) receptors (see below) produces antidepressant-like effects in preclinical models. The involvement of ionotropic glutamate receptors in the control of mood disorders and the mechanism of antidepressants has been studied much more extensively than the metabotropic glutamate receptors. However, recent attention has been directed to the potential role of the mGlu receptors.The mGlu receptors are classified into three groups, with eight subtypes: group I (mGlu1 and -5), group II (mGlu2 and -3), and group III (mGlu4, (Schoepp and Conn, 1993) base...

Metabotropic Glutamate Receptors: Potential Drug Targets for Psychiatric Disorders

“…Both compounds reduced immobility times in despair models, such as forced swim and tail suspension tests [88][89][90]. The antidepressant effects of MPEP in the forced swim test were no longer observed in knockout mice lacking mGlu5 receptors [88], indicating that these compounds exerted their effects via the mGlu5 receptor.…”

“…Both compounds reduced immobility times in despair models, such as forced swim and tail suspension tests [88][89][90]. The antidepressant effects of MPEP in the forced swim test were no longer observed in knockout mice lacking mGlu5 receptors [88], indicating that these compounds exerted their effects via the mGlu5 receptor. Moreover, subchronic administration of MPEP or MTEP attenuated abnormal behaviors (learning deficits in a passive avoidance paradigm or locomotor hyperactivity in a novel environment) induced by olfactory bulbectomy [89,91].…”

Transcriptional profiling of the rat frontal cortex following administration of the mGlu5 receptor antagonists MPEP and MTEP

“…However, some investigators have reported that multiple dosing procedures with these compounds produces increases efficacy in the anxiolytic, antidepressant or anti-addictive effects as compared with acute administration (Backstrom et al, 2004;Cowen et al, 2005;Klodzinska et al, 2004;Li et al, 2006;Nordquist et al, 2007;Pilc et al, 2002). This raises the possibility that changes in gene expression may underlie some of the behavioral effects of MPEP and/or MTEP following repeated exposure.…”

Depression Viewed as a GABA/Glutamate Imbalance in the Central Nervous System

“…Therefore, to begin with, attempts to investigate the potential antidepressant-like effect of the antagonists of mGlu 5 receptors were undertaken. As shown in Table 2 the selective orthosteric antagonist for this receptor, MPEP (Gasparini et al, 1999) and its derivative MTEP (Cosford et al, 2003), were active in the forced swim test in both rats and mice, and in the tail suspension test in mice (Belozertseva et al, 2007;Li et al, 2006;Palucha et al, 2005;Pilc et al, 2002;Tatarczyńska et al, 2001). Moreover, in the olfactory bulbectomy model of depression it was shown that chronic administration of those substances evoked behavioural effects similar to those observed after the administration of ADDs administration (Palucha et al, 2005;Pilc et al, 2002;Wieronska et al, 2005 in the hippocampus of the rat brain, which remains in line with the neurotrophic theory of depression (Legutko et al, 2006 The antidepressant effects could be evoked not only after administration of mGlu 5 receptor antagonists, but also after blockade of mGlu 1 receptor subtype, the second representative of group I mGlu receptors, as its antagonist EMQMCM was effective in the tail suspension and forced swim test in mice (Belozertseva et al, 2007).…”