title: Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine in rodents.
abstract: 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.
authors.affiliation: Novartis Pharma AG, Nervous System Research, Basel, Switzerland. willibrordus.spooren@pharma.novartis.com
authors.forename: W P
authors.initials: WP
authors.lastname: Spooren
authors.forename: A
authors.initials: A
authors.lastname: Vassout
authors.forename: H C
authors.initials: HC
authors.lastname: Neijt
authors.forename: R
authors.initials: R
authors.lastname: Kuhn
authors.forename: F
authors.initials: F
authors.lastname: Gasparini
authors.forename: S
authors.initials: S
authors.lastname: Roux
authors.forename: R D
authors.initials: RD
authors.lastname: Porsolt
authors.forename: C
authors.initials: C
authors.lastname: Gentsch
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D003913:Dextroamphetamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
chemical_list: D014151:Anti-Anxiety Agents; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; C121465:6-methyl-2-(phenylethynyl)pyridine; D003913:Dextroamphetamine