Evidence for the Role of Metabotropic Glutamate (mGlu)2 Not mGlu3 Receptors in the Preclinical Antipsychotic Pharmacology of the mGlu2/3 Receptor Agonist (–)-(1R,4S,5S,6S)-4-Amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic Acid (LY404039)

Abstract

In this article, we use mGlu receptor-deficient mice to investigate the relative contribution of mGlu2 and mGlu3 receptors in mediating the antipsychotic profile of LY404039 in the phencyclidine (PCP) and d-amphetamine (AMP) models of psychosis. To further explore the mechanism of action of LY404039, we compared the drugs' ability to block PCP-induced hyperlocomotion to that of atypical antipsychotics in wild-type and mice lacking mGlu2/3 receptors. In wild-type animals, LY404039 (3-30 mg/kg i.p.) significantly reversed AMP (5 mg/kg, i.p.)-induced increases in ambulations, distance traveled, and reduced time spent at rest. LY404039 reversed PCP (7.5 mg/kg i.p.)-evoked behaviors at 10 mg/kg. The antipsychotic-like effects of LY404039 (10 mg/kg i.p.) on PCP and AMP-evoked behavioral activation were absent in mGlu2 and mGlu2/3 but not in mGlu3 receptor-deficient mice, indicating that the activation of mGlu2 and not mGlu3 receptors is responsible for the antipsychotic-like effects of the mGlu2/3 receptor agonist LY404039. In contrast, the atypical antipsychotic drugs clozapine and risperidone inhibited PCP-evoked behaviors in both wild-type and mGlu2/3 receptor-deficient mice. These data demonstrate that the antipsychotic-like effects of the mGlu2/3 receptor agonist LY404039 in psychostimulant models of psychosis are mechanistically distinct from those of atypical antipsychotic drugs and are dependent on functional mGlu2 and not mGlu3 receptors.Schizophrenia is a lifelong and devastating psychiatric disorder characterized by positive, negative, and cognitive symptoms (Andreasen and Carpenter, 1993;Ross et al., 2006). Although several neurotransmitter systems (dopamine, serotonin, and glutamate) have been implicated in the pathophysiology of schizophrenia, dopamine D 2 receptors are the primary target of all antipsychotic drugs. Although these medications reduce the severity of positive symptoms, they have only a modest effect on the negative or cognitive impairments present in the disorder. Due to these shortcomings, there is a clear need for alternative strategies for the treatment of schizophrenia. Recent clinical data suggest that a group II metabotropic glutamate (mGlu) receptor agonist LY2140023 (prodrug of LY404039) has antipsychotic properties and may represent an alternative, nondopaminergic treatment for schizophrenia (Patil et al., 2007).

Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia

“…However, studies in mGuR2 and mGluR3 knock-out mice demonstrate that the heterotropic agonists act via mGluR2 to block the effects of PCP (31,34), whereas the effects of the 2-PMPA on PCP in these knock-out mice are mediated by NAAG activation of mGluR3 (26), consistent with a substantial body of data demonstrating that NAAG is an mGluR3-selective agonist (12). The data presented here on the NAAG peptidase inhibition-induced elevation of NAAG levels in the mPFC and NAc together with the resulting blockade of PCP-induced increases in glutamate release establish further the parallels between the effects of the heterotropic agonists and those of NAAG peptidase inhibitors in these schizophrenia models.…”

“…The efficacy of heterotropic agonists in this PCP model was observed in mGluR3 but not mGluR2 knock-out mice, consistent with their activation of mGluR2 in vitro (31)(32)(33)(34). Although mGluR2/3 agonists and mGluR2-positive allosteric modulators represent a potentially efficacious mGluR2-targeted antipsychotic therapy (35,36), data from animal models of schizophrenia suggest that NAAG peptidase inhibition represents a related but distinctly different pharmacotherapy based on activation of mGluR3 (12,26).…”

Glutamate receptor mGlu2 and mGlu3 knockout striata are dopamine supersensitive, with elevated D2High receptors and marked supersensitivity to the dopamine agonist (+)PHNO

“…Of course, an alternate conclusion is that the LY agonists may be ineffective in the mGlu2 KO mice because they act through mGlu2. However, the action of the LY drugs were only reported for phencyclidine doses of 3 and 5 mg/kg, but not at the maximum effective dose of 10 mg/kg phencyclidine (Fell et al, 2008;Woolley et al, 2008).…”

Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI

“…This is significant, as previous studies in mouse models predictive of antipsychotic potential have shown that mGluR2, not mGluR3, mediates the actions of mGlu2/3 receptor dual agonists. 15,16 Furthermore, modulation restricts receptor activation only to relevant tissues in the presence of endogenous agonist (glutamate) and reduces the potential for tachyphylaxis, which has been reported with GPCR agonists upon chronic treatment. 17 We have recently described a novel class of mGluR2 PAMs featuring aryl aza-benzimidazolones, culminating in the discovery of optimized compound 2 ( Figure 2).…”