Reduced stress-induced hyperthermia in mGluR5 knockout mice.
It hs been suggested that metabotropic glutamate receptor subtype 5 (mGluR5) play a role in the expression of anxiety, based on anxiolytic-like effects of the selective mGluR5 antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) in rodent models of anxiety, including stress-induced hyperthermia (SIH). To examine the suggested role of mGlu5 receptors in the expression of anxiety, we examined the stress response in mice lacking mGluR5 in several variations of the SIH procedure. In this paradigm, stress causes a mild increase in body temperature that can be blocked by known anxiolytic agents. Three procedures were employed: classical SIH using rectal-probe measurement of body temperature, and radiotelemetric measurement of body temperature in response to either saline injection or to the introduction of an intruder into the home cage. In all three procedures the mGluR5-knockout mice displayed a significant attenuation of the hyperthermic response to stress compared to littermate wild-type control mice. To confirm that our observations were likely to be due to the absence of mGluR5 in the knockout mice we also tested the effect of the recently described selective mGluR5 antagonist MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) in both the wild-type and mGluR5 knockout mice. Administration of MTEP in the wild-type mice, but not the mGluR5 knockout mice, attenuated SIH. That the mGluR5 knockout mice displayed an anxiolytic-like phenotype and that the mGluR5 antagonist, MTEP, showed a anxiolytic-like effect only in mice possessing mGluR5 further supports the suggestion that mGluR5 antagonists may be useful in the treatment of anxiety.
Brodkin
J
J
Merck Research Laboratories, MRLSDB1, 3535 General Atomics Court, San Diego, CA 92121, USA. Jesse_Brodkin@Merck.com
Bradbury
M
M
Busse
C
C
Warren
N
N
Bristow
L J
LJ
Varney
M A
MA
D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001831:Body Temperature / Q000187:drug effects / Q000235:genetics; D001923:Brain Chemistry / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005334:Fever / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013844:Thiazoles / Q000494:pharmacology
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles