Anxiolytic-like activity of the mGluR5 antagonist MPEP: a comparison with diazepam and buspirone.
The selective and systemically active antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), 2-methyl-6-(phenylethynyl)pyridine (MPEP) was shown to display anxiolytic-like activity in a number of unconditioned assays of stress and anxiety (elevated plus maze, shock probe burying, marble burying, social interaction, and stress-induced hyperthermia) in rodents. In this report, we extend these observations found using unconditioned models of anxiety to include three models of conditioned anxiety, comparing the activity of MPEP to the clinically used anxiolytics, diazepam, and buspirone. MPEP and diazepam, but not buspirone, showed anxiolytic-like activity in the fear-potentiated startle (FPS) model. In a conditioned ultrasonic vocalization (USV) procedure, MPEP, diazepam, and buspirone reduced vocalizations to a similar degree. In the modified Geller-Seifter procedure, MPEP, diazepam, and buspirone displayed statistically significant anxiolytic-like activity, increasing the number of punished responses. Thus, these findings confirm and extend previous reports that MPEP exhibits anxiolytic-like activity in rats, and suggests that development of mGluR5 antagonists may provide a novel approach to treating anxiety disorders.
Brodkin
Jesse
J
Merck Research Laboratories, MRLSD-B1, 3535 General Atomics Court, San Diego, CA 92121, USA. Jesse_Brodkin@Merck.com
Busse
Chris
C
Sukoff
Stacey J
SJ
Varney
Mark A
MA
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D002065:Buspirone / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005239:Fear / Q000523:psychology; D058785:GABA-A Receptor Agonists; D008297:Male; D011678:Punishment / Q000523:psychology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013216:Reflex, Startle / Q000187:drug effects; D014828:Vocalization, Animal / Q000187:drug effects
D014151:Anti-Anxiety Agents; D018691:Excitatory Amino Acid Antagonists; D058785:GABA-A Receptor Agonists; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C121465:6-methyl-2-(phenylethynyl)pyridine; D003975:Diazepam; D002065:Buspirone