Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

Abstract

Pharmacological manipulation of N-methyl-D-aspartate (NMDA) receptors may be critical for the treatment of many neurological and psychiatric disorders. Metabotropic glutamate (mGlu5) receptors are abundant in corticolimbic circuitry, where they modulate NMDA receptor-mediated signal transduction. Therefore, pharmacological manipulation of mGlu5 receptor may provide a treatment strategy for cognitive disorders that are associated with NMDA receptor dysfunction. We sought to determine whether the recently described molecular and cellular interactions between NMDA and mGlu5 receptors coregulate higher order behaviors. We examined the interaction of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and the use-dependent NMDA antagonist MK-801, on locomotion, stereotypy, working memory, instrumental learning, and corticolimbic dopamine release. MPEP, at 10 mg/kg, but not 3 mg/kg, impaired working memory and instrumental learning, transiently increased dopamine release in prefrontal cortex and nucleus accumbens, and augmented the effect of MK-801 on cortical dopamine release, locomotion, and stereotypy. Pretreatment with 3 mg/kg of MPEP enhanced the detrimental effects of MK-801 on cognition. These results demonstrate that an mGlu5 receptor antagonist can potentiate the motoric, cognitive, and dopaminergic effects of an NMDA receptor antagonist. Thus, mGlu5 receptors appear to play a major role in regulating NMDA receptor-dependent cognitive functions such as learning and working memory. By extension, these results suggest that pharmacological potentiation of mGlu5 receptors may ameliorate the cognitive and other behavioral abnormalities associated with NMDA receptor deficiency.

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

“…A functional interactions between mGluR5 and NMDAR is well supported by the literature (Salter and Kalia, 2004) and our own data (Jia et al, 1998;Huang et al, 2001;Hannan et al, 2001). Indeed, several observations have shown that agonists and antagonists of mGluR5 may, respectively, attenuate and potentiate the effects of NMDAR antagonists in vivo (Kozela et al, 2003;Kinney et al, 2003;Homayoun et al, 2004). As mGluR5 antagonist administered alone could not disrupt PPI, but could enhance the effects of PCP (Kinney et al, 2003), it is possible that the PPI deficit in mGluR5 mutants might result from an interaction between NMDAR hypofunction together with missing mGluR5 complex rather than the alternative of only a parallel pathway downstream of mGluR5.…”

“…The mGluR5 binds through G-dependent or independent pathways (Heuss et al, 1999) with predominantly couple via Gq to phospholipase C. This yields diacylglycerol, which activates protein kinase C (PKC), and inositol-1,4,5-triphosphate, which releases intracellular Ca 2 + (Conn and Pin, 1997), and this in turn can increase NMDAR-evoked responses in a variety of neuronal tissues (Doherty et al, 1997;Awad et al, 2000), indicating one potential functional link between mGluR5 and NMDAR. Indeed, administration of mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyradine (MPEP) facilitated in vivo effects of NMDAR antagonists in rodents, producing anxiolytic (Spooren et al, 2000), neuroprotective (Bruno et al, 2000), and anticonvulsant (Chapman et al, 2000) effects, disrupting prepulse inhibition (PPI) (Kinney et al, 2003) and enhancing the detrimental effects of MK-801 on cognition and stereotypy (Homayoun et al, 2004). This demonstrates that mGluR5 play a major role in regulating NMDAR-dependent function.…”

“…The administration of mGluR5 antagonistFMPEP to rats disrupted LI based on conditioned taste aversion (Bills et al, 2005). In addition, cognitive deficits relevant to schizophrenia were observed after MPEP treatment of rats in the spontaneous alteration test of working memory (Homayoun et al, 2004), which is among the most commonly observed cognitive impairments in schizophrenia patients (Goldman-Rakic, 1994).…”

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

“…For this reason, schizophrenia has been associated with NMDA receptor hypofunction (Javitt and Zukin, 1991;Tamminga, 1998). In rats, PCP and the more potent and selective noncompetitive NMDA antagonist, dizocilpine (MK-801), bring about hyperlocomotion and stereotypies (Hertel et al, 1996;Adams and Moghadam, 2001;Homayoun et al, 2004). These behaviors are thought to result from increased dopaminergic and serotonergic activities (Giros et al, 1996;Jentsch et al, 1998;Lucki, 1998), and have been potentially related to positive symptoms of schizophrenia (Moghaddam and Adams, 1998;Jentsch and Roth, 1999;Mohn et al, 1999).…”

Positive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex

“…Conversely, the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) potentiates the effects of NMDA receptor antagonists on spontaneous burst and spike activity of cortical neurons (Homayoun and Moghaddam 2006). Behavioral studies also show that MPEP enhances the effects of NMDA antagonist blockade on prepulse inhibition, locomotion, working memory, and instrumental learning impairments (Campbell et al 2004;Homayoun et al 2004;Kinney et al 2005a;Spooren et al 2000). The worsening of the detrimental effects of NMDA receptor antagonists by mGlu5 receptor antagonist suggests that activation of mGlu5 receptors may represent a plausible approach for ameliorating symptoms of schizophrenia (Marino and Conn 2002;Moghaddam 2004).…”