Inhibitory effects of MPEP, an mGluR5 antagonist, and memantine, an N-methyl-D-aspartate receptor antagonist, on morphine antinociceptive tolerance in mice

In order to test the possible role of mGluR5 signaling in the behavioral endophenotypes of schizophrenia and other psychiatric disorders, we used genetic engineering to create mice carrying null mutations in this gene. Compared to their mGluR5 + / + littermates, mGluR5 À/À mice have disrupted latent inhibition (LI) as measured in a thirst-motivated conditioned emotional response procedure. Administration of the positive modulator of a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPAR), CX546, during the conditioning phase only, improved the disrupted LI in mGluR5 knockout mice and facilitated LI in control C57BL/6J mice, given extended number of conditioning trails (four conditioning stimulus-unconditioned stimulus). Prepulse inhibition (PPI) was impaired in mGluR5 À/À mice to a level that could not be disrupted further by the antagonist of N-methyl-D-aspartate receptorsFMK-801. PPI deficit of mGluR5 À/À mice was effectively reversed by CX546, whereas aniracetam had a less pronounced effect. These data provide evidence that a potent positive AMPAR modulator can elicit antipsychotic action and represents a new approach for treatment of schizophrenia. Neuropsychopharmacology (2007) 32, 745-756.

Section: Discussionsupporting

confidence: 61%

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

Lipina

Weiss

Roder

2006

“…For example, there is an interaction between mGlu5 and NMDA receptor antagonists on morphine antinociceptive tolerance (Kozela et al, 2003), phencyclidine-induced hyperlocomotion, and disruption of prepulse inhibition (Henry et al, 2002;Kinney et al, 2002Kinney et al, , 2003. Together with the present data, these studies suggest that selective modulation of glutamatergic transmission through mGlu5 receptors can be used as a pharmacological strategy for the treatment of brain disorders that involve NMDA receptor dysfunction.…”

Section: Discussionsupporting

confidence: 61%

“…The selective mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocks NMDA-induced membrane depolarization in striatal spiny neurons and in cortical wedges (Pisani et al, 1997;Attucci et al, 2001). Systemically administered mGlu5 and NMDA receptor antagonists produce similar anxiolytic (Spooren et al, 2000;Chojnacka-Wojcik et al, 2001), neuroprotective (Bruno et al, 2000), anticonvulsant (Chapman et al, 2000), and tolerance blocking (Kozela et al, 2003) effects, and disrupt prepulse inhibition (Henry et al, 2002;Kinney et al, 2002). Therefore, modulation of mGlu5 receptors may be an effective therapeutic strategy for manipulation of NMDA receptor-mediated neurotransmission in disorders such as schizophrenia (Tamminga, 1998;Goff and Coyle, 2001; Krystal et al, 2003;Moghaddam, 2003) and addiction (Wolf, 1998), where NMDA receptor dysfunction is suspected.…”

Section: Introductionmentioning

confidence: 99%

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

Homayoun

Stefani

Adams

et al. 2004

237

182

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.

“…This functional coupling could result from the postsynaptic association of NMDA receptors with a complex of proteins, which includes different scaffolding proteins (eg PSD-95, Homer, Shank), but other receptors including mGluR5 are also linked to this complex (Kotecha et al, 2003), and activation of mGluR5 can lead to an enhancement of NMDA receptor function through phosphorylation by protein kinase C (Hermans and Challiss, 2001;Schoepp and Conn, 1993). The high affinity of MPEP for mGluR5 receptors, which is more than 1000-fold higher compared to NMDARs, makes it very unlikely that under the used conditions MPEP affects NMDARs directly (Oleary et al, 2000;Gubellini et al, 2001;Spooren et al, 2001;Kozela et al, 2003). In summary, the functional coupling of mGluR5 and NMDA receptor suggests that the blockade of mGluR5 by MPEP reduces glutamatergic signaling through NMDA receptors and thereby interacts with ethanol-seeking and relapse behavior.…”

Section: Discussionmentioning

confidence: 99%

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

Bäckström

Bachteler

Koch

et al. 2003

235

178

The glutamatergic system plays an important role in mediating neurobehavioral effects of ethanol. Metabotropic glutamate receptors subtype 5 (mGluR5) are modulators of glutamatergic neurotransmission and are abundant in brain regions known to be involved in ethanol self-administration. Here, we studied the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a highly potent, noncompetitive mGlu5 receptor antagonist, on voluntary ethanol consumption and relapse behavior. For this purpose, we used two models for the measurement of relapse behavior: (i) reinstatement of ethanol-seeking behavior by drug-associated cues and (ii) the alcohol deprivation effect in long-term ethanol-consuming rats. In the first set of experiments, rats were trained to lever press for ethanol in the presence of a distinct set of cues. After extinction, the animals were exposed to the respective cues that initiated reinstatement of responding. A response-contingent ethanol prime further enhanced responding compared to the conditioned cues alone. Under these conditions, MPEP (0, 1, 3, and 10 mg/kg) attenuated ethanol seeking significantly and in a dose-related manner. However, at the highest dose, MPEP also decreased the number of inactive lever responses. In the second set of experiments, rats with 1 year of ethanol experience and repeated deprivation phases were used. A subchronic treatment with MPEP (twice daily; 0, 3, and 10 mg/kg) resulted in a significant and dose-dependent reduction of the alcohol deprivation effect (ADE). Although the same MPEP treatment regimen decreased baseline drinking, this effect was not as pronounced as on the ADE. These results show in two commonly used models of relapse to ethanol that pharmacological targeting of mGlu5 receptors may be a promising approach for the treatment of alcoholism.