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

Author:

Menezes M. M.1,Santini M. A.2,Benvenga M. J.1,Marek G. J.13,Merchant K. M.1,Mikkelsen J. D.2,Svensson K. A.1

Affiliation:

1. Neuroscience Discovery, Eli Lilly & Company, Indianapolis, IN 46285, USA

2. Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark

3. Abbott Laboratories, Global Pharmaceutical Research and Development, Neuroscience Clinical Development, Abbott Park, IL 60064-6075, USA

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.

Funder

Danish Strategic Research Council

Publisher

Hindawi Limited

Subject

Energy Engineering and Power Technology,Fuel Technology

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