The mGlu2/3 Receptor Agonists LY354740 and LY379268 Differentially Regulate Restraint-Stress-Induced Expression of c-Fos in Rat Cerebral Cortex.

M M Menezes,M A Santini,J D Mikkelsen,G J Marek,K M Merchant,K A Svensson,M J Benvenga

doi:10.1155/2013/736439

Abstract

Metabotropic glutamate 2/3 (mGlu2/3) receptors have emerged as potential therapeutic targets due to the ability of mGlu2/3 receptor agonists to modulate excitatory transmission at specific synapses. LY354740 and LY379268 are selective and potent mGlu2/3 receptor agonists that show both anxiolytic- and antipsychotic-like effects in animal models. We compared the efficacy of LY354740 and LY379268 in attenuating restraint-stress-induced expression of the immediate early gene c-Fos in the rat prelimbic (PrL) and infralimbic (IL) cortex. LY354740 (10 and 30 mg/kg, i.p.) showed statistically significant and dose-related attenuation of stress-induced increase in c-Fos expression, in the rat cortex. By contrast, LY379268 had no effect on restraint-stress-induced c-Fos upregulation (0.3–10 mg/kg, i.p.). Because both compounds inhibit serotonin 2A receptor (5-HT2AR)-induced c-Fos expression, we hypothesize that LY354740 and LY379268 have different in vivo properties and that 5-HT2AR activation and restraint stress induce c-Fos through distinct mechanisms.

Highlights

Preclinical and clinical studies indicate that modulation of glutamatergic activity in the brain may have therapeutic value for the treatment of schizophrenia and anxiety-related disorders [1, 2]
Activation of presynaptic mGlu2 receptors with Metabotropic glutamate 2/3 (mGlu2/3) agonists negatively modulates the release of glutamate providing a feedback that prevents excessive glutamate release [5, 6]
Restraint stress significantly increased the number of positive cells containing c-Fos immunoreactivity relative to vehicle in both the PrL and IL cortex (P < 0.001; Figures 2, 3, and 4)

Summary

Introduction

Preclinical and clinical studies indicate that modulation of glutamatergic activity in the brain may have therapeutic value for the treatment of schizophrenia and anxiety-related disorders [1, 2]. Glutamate acts through ligand-gated ion channels and G-protein-coupled metabotropic glutamate (mGlu) receptors. Activation of presynaptic mGlu receptors with mGlu2/3 agonists negatively modulates the release of glutamate providing a feedback that prevents excessive glutamate release [5, 6]. The actions of multiple mGlu2/3 agonists and mGlu positive allosteric modulators (PAMs) have been explored in animal models predictive of antipsychotic and anxiolytic activity. LY354740 and LY379268 block PCP- and amphetamine-induced hyperlocomotion [8], two commonly used models of the positive symptoms of schizophrenia. Both compounds show efficacy in alleviating cognitive deficits induced by PCP. LY354740 improved the detrimental effects of PCP on the performance in a T-maze task [9], while LY379268 attenuated a PCP-induced cognitive deficit in the 5-choice serial reaction task [10]

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Conclusion