mGlu2/3 Agonist-Induced Hyperthermia: An In Vivo Assay for Detection of mGlu2/3 Receptor Antagonism and its Relation to Antidepressant-Like Efficacy in Mice

Author(s): S.D. Gleason, X. Li, I.A. Smith, J.D. Ephlin, X-S. Wang, B. A. Heinz, J.H. Carter, M. Baez, J. Yu, D.M. Bender, J.M. Witkin.

Journal Name: CNS & Neurological Disorders - Drug Targets

Volume 12 , Issue 5 , 2013

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Abstract:

An assay to detect the on-target effects of mGlu2/3 receptor antagonists in vivo would be valuable in guiding dosing regimens for the exploration of biological effects of potential therapeutic import. Multiple approaches involving blockade of mGlu2/3 receptor agoinist-driven behavioral effects in mice and rats were investigated. Most of these methods failed to provide a useful method of detection of antagonists in vivo (e.g., locomotor activity). In contrast, the mGlu2/3 receptor agonist LY379268 produced dose-dependent increases in body temperature of mice. The hyperthermic effects of LY379268 was abolished in mGlu2 and in mGlu2/3 receptor null mice but not in mGlu3 null mice. Hyperthermia was not produced by an mGlu8 receptor agonist. Agonist-induced hyperthermia was prevented in a dosedependent manner by structurally-distinct mGlu2/3 receptor antagonists. The blockade was stereo-specific. Moreover, this biological readout was responsive to both orthosteric and to negative allosteric modulators of mGlu2/3 receptors. Antagonism of agonist-induced hyperthermia predicted antidepressant-like efficacy in the mouse forced swim test. As with the hyperthermic response, the antidepressant-like effects of mGlu2/3 receptor antagonists were shown to be due to mGlu2 and not to mGlu3 or mGlu8 receptors through the use of receptor knock-out mice. The ability to rapidly assess ontarget activity of mGlu2/3 receptor antagonists enables determination of parameters for setting efficacy doses in vivo. In turn, efficacy-related data in the preclinical laboratory can help to set expectations of therapeutic potential and dosing in humans.

Keywords: mGlu2/3 receptor, LY341495, MGS0039, LY379268, hyperthermia, forced-swim, mouse.

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Article Details

VOLUME: 12
ISSUE: 5
Year: 2013
Page: [554 - 566]
Pages: 13
DOI: 10.2174/18715273113129990079

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