The mGlu₅ positive allosteric modulator LSN2463359 differentially modulates motor, instrumental and cognitive effects of NMDA receptor antagonists in the rat

Abstract

Metabotropic glutamate 5 (mGlu₅) receptors are known to functionally interact with N-methyl-d-aspartate (NMDA) receptors at both neuronal and behavioural levels, in a manner that may be of relevance to the treatment of schizophrenia. We have previously described a novel mGlu₅ positive allosteric modulator (PAM), LSN2463359 and provided evidence of its ability to attenuate aspects of the behavioural response to administration of the competitive NMDA receptor antagonist, SDZ 220,581. In addition, LSN2463359 was found to selectively attenuate reversal learning deficits observed in the neurodevelopmental MAM E17 model but not in the acute phencyclidine (PCP) model. In the present study, the interactions between this mGlu₅ PAM and the NMDA receptor were explored further by assessing the effects of LSN2463359 against some of the motor, instrumental and cognitive effects induced by the non-competitive NMDA receptor antagonists PCP and MK-801, the competitive NMDA receptor antagonist SDZ 220,581 and the GluN2B selective NMDA receptor antagonist, Ro 63-1908. LSN2463359 had either no or minor impact on locomotor hyperactivity induced by either PCP or SDZ 220,581. However, in rats lever pressing for food rewards under a variable interval 30s schedule of instrumental responding, the drug clearly attenuated not only the suppression of response rate induced by SDZ 220,581 but also the stimulation of response rate induced by Ro 63-1908. In contrast, LSN2463359 failed to alter both of the instrumental effects induced by the open channel blockers PCP and MK-801. In addition, although PCP and SDZ 220,581 induced similar deficits in a discrimination and reversal learning task, LSN2463359 was again only able to reverse the deficit induced by SDZ 220,581. The results indicate that the interactions between mGlu₅ and NMDA receptors are dependent on both the mechanism of the blockade of the receptor and the behavioural domain under investigation. Our work has implications for the preclinical use of NMDA receptor antagonists in the prediction of potential therapeutic efficacy in the search for novel treatments for schizophrenia. Positive allosteric modulators of the mGlu₅ receptor certainly question the predictive validity of such approaches.

This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Introduction

The glutamatergic hypothesis of schizophrenia originated from the discovery that the psychotomimetic agents, phencyclidine (PCP) and ketamine are antagonists of the N-methyl-d-aspartate (NMDA) receptor (Anis et al., 1983) capable of inducing psychotic states in volunteers and exacerbating the core psychotic and cognitive symptoms of patients with schizophrenia (Luby et al., 1959; Javitt and Zukin, 1991; Krystal et al., 1994; Lahti et al., 1995; Malhotra et al., 1996, 1997; Adler et al., 1998; Newcomer et al., 1999; Hetem et al., 2000; Krystal et al., 2000; Parwani et al., 2005). Now, several other lines of evidence suggest impaired NMDA receptor function in the pathophysiology of schizophrenia (Javitt and Zukin, 1991; Olney and Farber, 1995; Olney et al., 1999; Kristiansen et al., 2007; Zandi et al., 2011), which naturally prompts the hypothesis that restoration of NMDA receptor function might alleviate its symptoms. While direct pharmacological activation of NMDA receptors might be feasible, it is unlikely to be a viable treatment option because of the possibility of serious adverse events related to NMDA receptor overactivation, such as seizures and excitotoxicity (Lynch and Guttmann, 2002). An “indirect” activation of the NMDA receptor via glycine site modulation (Parsons et al., 1998; Wood, 2005; Yang and Svensson, 2008; Labrie and Roder, 2010) might be possible, although another alternative approach to the regulation of NMDA-mediated glutamatergic function would be to target metabotropic glutamate (mGlu) receptors (Moghaddam, 2004; Conn et al., 2009; Vinson and Conn, 2012). In particular, the mGlu₅ receptor subtype is a close postsynaptic signalling partner of the NMDA receptor (Stoop et al., 2003; Homayoun and Moghaddam, 2006). Activation of mGlu₅ receptors might therefore play an important role in enhancing NMDA receptor function in several brain regions of relevance to schizophrenia, with both in vitro and in vivo evidence from the hippocampus, striatum and prefrontal cortex suggesting this to be the case (Doherty et al., 1997, 2000; Awad et al., 2000; Attucci et al., 2001; Mannaioni et al., 2001; Pisani et al., 2001; Kinney et al., 2003; Collett and Collingridge, 2004; Kinney et al., 2005, 2006; Homayoun and Moghaddam, 2006; Lecourtier et al., 2007). Potential clinical applications in terms of antipsychotic efficacy of several mGlu₅ positive allosteric modulator (PAM) molecules, such as CDPPB and ADX47273 have recently been reported (Kinney et al., 2005; Liu et al., 2008; Schlumberger et al., 2009, 2010; Stefani and Moghaddam, 2010).

We recently reported preclinical evidence for two novel mGlu₅ PAMs, LSN2463359 and LSN2814617, with possible utility for the treatment of schizophrenia (Gilmour et al., in this issue). However, our initial studies raised an immediate question that the specificity of the effects of these molecules might partly depend on the rodent model of schizophrenia against which the molecules are assessed since LSN2463359 selectively attenuated reversal learning deficits observed in the neurodevelopmental MAM E17 model but not in the acute PCP model (Gastambide et al., 2012). In contrast to the lack of effect of LSN2463359 against a PCP-induced deficit, we have also previously observed that this molecule can attenuate behavioural deficits in instrumental responding and delayed matching to position induced by the competitive NMDA receptor antagonist SDZ 220,581 (Gilmour et al., in this issue). Thus, two issues are raised by this work – the nature of both the pharmacological mechanism of disruption and the behavioural domain under assessment – that need to be clarified in order to describe the behavioural effects of mGlu₅ potentiators more precisely. To investigate this further, we assessed LSN2463359 (N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide) for its ability to modulate some of the motor, instrumental and cognitive effects induced by different classes of NMDA receptor antagonists, including those acting competitively and non-competitively, that may have relevance to some of the positive, negative and cognitive symptoms of schizophrenia.