Anxiolytic-Like Effects of the Prototypical Metabotropic Glutamate Receptor 5 Antagonist 2-Methyl-6-(phenylethynyl)pyridine in Rodents

• Published in: The Journal of pharmacology and experimental therapeutics 2000-12, Vol.295 (3), p.1267-1275
• Main Authors: Spooren, W P, Vassout, A, Neijt, H C, Kuhn, R, Gasparini, F, Roux, S, Porsolt, R D, Gentsch, C
• Format: Article
• Language: English
• Subjects: Animals; Anti-Anxiety Agents - pharmacology; Body Temperature - drug effects; Dextroamphetamine - pharmacology; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists - pharmacology; Exploratory Behavior - drug effects; Male; Maze Learning - drug effects; Mice; Motor Activity - drug effects; Pyridines - pharmacology; Rats; Rats, Inbred BN; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Metabotropic Glutamate - antagonists & inhibitors
• ISSN: 0022-3565; 1521-0103

Recently, selective and systemically active antagonists for the metabotropic glutamate 5 receptor (mGlu 5 ) were discovered, and the most potent derivative was found to be MPEP (2-methyl-6-(phenylethynyl)pyridine). Given the high expression of mGlu 5 receptors in limbic forebrain regions, it was decided to evaluate the anxiolytic potential of MPEP. After an acute oral administration, MPEP attenuated the anxiety-dependent variable in a variety of well established anxiety test paradigms. In rats, MPEP (10, 30, and 100 mg/kg) increased punished responses in the Geller-Seifter test, but none of these effects reached statistical significance. MPEP significantly increased the ratio (open/total arm entries; 0.1, 1, and 10 mg/kg), the number of open arm entries (0.1, 1, and 10 mg/kg), as well as time spent on open arm (0.1 and 1 mg/kg) in the elevated plus maze test. Furthermore, MPEP (0.3 and 1 mg/kg) significantly increased the time spent in social contact in the social exploration test. In mice, MPEP attenuated stress-induced hyperthermia (15 and 30 mg/kg) and decreased the number of buried marbles in the marble burying test (7.5 and 30 mg/kg). Finally, MPEP (0.01, 0.1, 1, 10, and 100 mg/kg) was tested on spontaneous locomotor activity in mice, and only a dose of 100 mg/kg significantly reduced vertical activity; no effect was seen on horizontal activity. MPEP (7.5, 15, and 30 mg/kg) was ineffective on d -amphetamine-induced (2.5 mg/kg) locomotor activity in mice and prepulse inhibition in rats (1, 3, or 10 mg/kg). Thus, these findings indicate that MPEP exhibits anxiolytic-like effects and low risks for sedation and psychotomimetic side-effects in rodents.