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