The ampakine CX546 restores the prepulse inhibition and latent inhibition deficits in mGluR5-deficient 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(-/-) mice have disrupted latent inhibition (LI) as measured in a thirst-motivated conditioned emotional response procedure. Administration of the positive modulator of alpha-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(-/-) mice to a level that could not be disrupted further by the antagonist of N-methyl-D-aspartate receptors - MK-801. PPI deficit of mGluR5(-/-) 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.
Lipina
Tatiana
T
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada. lipina@mshri.on.ca
Weiss
Karin
K
Roder
John
J
D000161:Acoustic Stimulation / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D003214:Conditioning, Classical / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004597:Electroshock / Q000009:adverse effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects* / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency*; D013216:Reflex, Startle / Q000187:drug effects* / Q000235:genetics
C443080:1-(1,4-benzodioxan-6-ylcarbonyl)piperidine; D000928:Antidepressive Agents; D004149:Dioxoles; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D010880:Piperidines; D011760:Pyrrolidinones; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C036466:aniracetam; D016291:Dizocilpine Maleate