title: 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.
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 dose-dependent 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 on-target 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.
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Gleason
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: I A
authors.initials: IA
authors.lastname: Smith
authors.forename: J D
authors.initials: JD
authors.lastname: Ephlin
authors.forename: X-S
authors.initials: XS
authors.lastname: Wang
authors.forename: B A
authors.initials: BA
authors.lastname: Heinz
authors.forename: J H
authors.initials: JH
authors.lastname: Carter
authors.forename: M
authors.initials: M
authors.lastname: Baez
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.forename: D M
authors.initials: DM
authors.lastname: Bender
authors.forename: J M
authors.initials: JM
authors.lastname: Witkin
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003216:Conditioning, Operant / Q000187:drug effects; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D018683:Excitatory Amino Acid Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005106:Exploratory Behavior / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009068:Movement / Q000187:drug effects; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D018683:Excitatory Amino Acid Agents; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3