P.1.c.015 Differential effects of acute and sub-chronic PCP in rodent cognition: reversal with a selective mGlu2 negative allosteric modulator RO4491533

Abstract

Abnormalities in electroencephalogram gamma oscillations have been implicated in schizophrenic symptoms. N-methyl-d-aspartate (NMDA) receptor antagonists produce behavioral abnormalities that are similar to the symptoms of schizophrenia, including social and cognitive impairment, and also increase the power of spontaneous gamma oscillations in the frontal cortex in rodents. Both mGlu2/3 receptor agonists and mGlu1 receptor antagonists reportedly improve behavioral abnormalities elicited by NMDA receptor antagonists in rodents. The present study evaluated the effects of an mGlu2/3 receptor agonist and an mGlu1 receptor antagonist on aberrant basal gamma oscillations elicited by an NMDA receptor antagonist, ketamine, in the rat frontal cortex. Ketamine increased spontaneous cortical gamma oscillations. Pretreatment with an mGlu2/3 receptor agonist, (−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), or an mGlu1 receptor antagonist, (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685), reduced the ketamine-induced basal gamma hyperactivity. These findings indicate that the stimulation of mGlu2/3 receptors and the inhibition of mGlu1 receptors reverse aberrant gamma oscillations, and these effects may partially explain the antipsychotic-like properties of mGlu2/3 receptor agonists and mGlu1 receptor antagonists.