Selective Remediation of Reversal Learning Deficits in the Neurodevelopmental MAM Model of Schizophrenia by a Novel mGlu5 Positive Allosteric Modulator

Abstract

Based on the glutamatergic hypothesis of schizophrenia we assessed the effects of a novel mGlu5 positive allosteric modulator, LSN2463359 [N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide] on deficits in cognitive flexibility in two distinct rodent models of schizophrenia, the neurodevelopmental MAM E17 model and the acute PCP model. Cognitive flexibility was measured with the intra-dimensional and extra-dimensional set-shifting and reversal learning digging paradigm. Regional effects of MAM on the expression of parvalbumin-positive cells (PV) and mGlu5 receptors were also examined, to further characterize the model. Results showed that LSN2463359 selectively attenuated reversal learning deficits in the MAM but not acute PCP model. Whilst both models led to deficits in reversal learning and extra-dimensional set-shifting, the reversal impairments were qualitatively distinct, with MAM increasing perseverative responding, whereas the PCP deficit was mainly due to the inability of rats to maintain reinforced choice behavior. Reduction of PV and mGlu5 expression was found in the MAM model in several regions of importance in schizophrenia, such as the orbitofrontal and medial prefrontal cortex, which also mediate reversal learning and extra-dimensional set-shifting. The present findings confirm that the positive modulation of mGlu5 receptors may have beneficial effects in the treatment of certain aspects of cognitive impairment associated with schizophrenia. This study also illustrates the importance of studying putative cognitive enhancing drug effects in a number of models which may have implications for the future development of the compound.

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

“…Furthermore, recent studies reveal that pure mGlu 5 PAMs have clear advantages over mGlu 5 agonists in terms of their safety profiles (Rook et al, 2013). Several different mGlu 5 PAM chemotypes have been identified, and previous studies have shown that mGlu 5 PAMs from different scaffolds exhibit efficacy in animal models predictive of antipsychotic-like and cognition-enhancing activity (Kinney et al, 2005;Liu et al, 2008b;Spear et al, 2011;Gastambide et al, 2012;Gastambide et al, 2013;Gilmour et al, 2013). Herein, we describe the in vitro and behavioral characterization of two N-aryl piperazine mGlu 5 PAMs: 2-(4-(2-(benzyloxy)acetyl)piperazin-1-yl)benzonitrile (VU0364289), which was discovered in-house from an evolved high-throughput screening negative allosteric modulator lead , and 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone (DPFE) (disclosed in a patent application by AstraZeneca and NPS [WO 2007/087135;Slassi et al, 2007]), both structural analogs of the recently published mGlu 5 PAM, CPPZ (Spear et al, 2011;Xiong et al, 2010).…”

Activation of the mGlu5 Receptor for the Treatment of Schizophrenia and Cognitive-Deficit-Associated Disorders

“…On another hand, LSN246339 failed to attenuate reversal learning deficit induced by PCP [73]. The lack of effect in the latter test might be related to the pharmacological mechanism of learning deficit, as LSN246339 attenuated reversal learning deficit associated with the competitive NMDA antagonist SDZ 220,581 [73]. In fact, in this experiment LSN246339 reduced perseverative deficits and reduced the number of regressive errors [73].…”

“…However, 47 was found to improve performance in the variable interval 30 s task and the DMTP task in rats treated with the competitive NMDA receptor antagonist SDZ 220,581, albeit with a U-shaped dose-response curve in the 1-10 mg/kg dose range. As well, 47 attenuated deficits in cognitive flexibility in the neurodevelopmental MAM model of schizophrenia, but not in the acute PCP model [73]. It was also found that 2.5, 5, and 10 mg/kg doses significantly increased wakefulness in rats, as determined by EEG monitoring.…”

“…On the one hand, in a neurodevelopmental model of schizophrenia based on the disruption of neurogenesis on gestational day 17 with MAM (methyl azoxy methanol E17 model; [124,125]), LSN246339 20 selectively attenuated reversal learning deficits [73]. On another hand, LSN246339 failed to attenuate reversal learning deficit induced by PCP [73].…”

“…On the one hand, in a neurodevelopmental model of schizophrenia based on the disruption of neurogenesis on gestational day 17 with MAM (methyl azoxy methanol E17 model; [124,125]), LSN246339 20 selectively attenuated reversal learning deficits [73]. On another hand, LSN246339 failed to attenuate reversal learning deficit induced by PCP [73]. The lack of effect in the latter test might be related to the pharmacological mechanism of learning deficit, as LSN246339 attenuated reversal learning deficit associated with the competitive NMDA antagonist SDZ 220,581 [73].…”