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

Abstract

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.

Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5

“…Following enrichment, the response to MK-801 in mGlu5 KO mice was potentiated, with KO mice showing significantly higher levels of hyperactivity compared with KO mice housed in standard conditions. In agreement with the previous finding, the current work demonstrated impaired PPI in mGlu5 KO mice to a level that was not disrupted further by MK-801 (Lipina et al, 2007). This is unlikely to be a 'floor' effect caused by reduced baseline levels of PPI in mGlu5 KO mice, as it has been shown that higher doses of MK-801 than those used in the present study can elicit further disruptions in PPI in mGlu5 KO mice compared with saline controls, suggesting that KO mice show a reduced sensitivity to the drug rather than a complete resistance (Lipina et al, 2007).…”

“…In agreement with the previous finding, the current work demonstrated impaired PPI in mGlu5 KO mice to a level that was not disrupted further by MK-801 (Lipina et al, 2007). This is unlikely to be a 'floor' effect caused by reduced baseline levels of PPI in mGlu5 KO mice, as it has been shown that higher doses of MK-801 than those used in the present study can elicit further disruptions in PPI in mGlu5 KO mice compared with saline controls, suggesting that KO mice show a reduced sensitivity to the drug rather than a complete resistance (Lipina et al, 2007). Thus, the present results cannot be explained simply by altered baseline PPI in standard-housed or environmentally-enriched KO mice.…”

“…PPI disruption and locomotor hyperactivity in mGlu5 KO mice have also been shown to be normalized by chronic administration of clozapine, accompanied by an increase in NMDAR binding (Gray et al, 2009). Enhancement of glutamatergic signaling via the NMDAR glycine site and the AMPA receptor similarly ameliorates PPI in mGlu5 KO mice (Lipina et al, 2007;Chen et al, 2010). Here we show that environmental enrichment also ameliorates PPI, potentially drawing a parallel between the therapeutic effects of a positive environment and pharmacological treatment.…”

“…mGlu5 KO mice also demonstrate impaired PPI (Kinney et al, 2003; and the amelioration of this deficit by chronic administration of clozapine is accompanied by an increase in NMDAR binding (Gray et al, 2009). Acute mGlu5 antagonism potentiates PPI disruption by NMDAR antagonists (Kinney et al, 2003;Pietraszek et al, 2005), and mGlu5 KO mice show reduced sensitivity to MK-801-induced PPI disruptions (Lipina et al, 2007). Further evidence of NMDAR dysfunction in mGlu5 KO mice has been suggested by the loss of NMDAR-mediated components of hippocampal CA1 LTP (Lu et al, 1997;Jia et al, 1998).…”

“…For example, treatment with the mGlu5 antagonists, MPEP and MTEP, augments the hyperlocomotive effects of PCP and MK-801 (Henry et al, 2002;Campbell et al, 2004;Pietraszek et al, 2005) while mGlu5 knockout (KO) mice show baseline hyperactivity and a hypersensitivity to MK-801-induced hyperlocomotion (Lipina et al, 2007;Gray et al, 2009). mGlu5 KO mice also demonstrate impaired PPI (Kinney et al, 2003; and the amelioration of this deficit by chronic administration of clozapine is accompanied by an increase in NMDAR binding (Gray et al, 2009).…”