Anxiolytic-like activity of the mGluR5 antagonist MPEP

Abstract

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.

Introduction

Benzodiazepines are the most commonly prescribed anxiolytic drugs, being efficacious against a spectrum of anxiety disorders. However, there are issues with addiction, tolerance, and dependence/withdrawal, as well as adverse side effects that include sedation, cognitive and psychomotor impairment, and anterograde amnesia. The other major classes of compounds used to treat anxiety are selective serotonin reuptake inhibitors (SSRIs) and the 5HT-1A partial agonist, buspirone. However, both classes of compounds have a slow onset of action (4–6 weeks) and their own side profiles. There is therefore a need for anxiolytics that show a rapid onset of action and an efficacy similar to benzodiazepines, with a low abuse potential and minimal impairment of cognition and motor skills. Since benzodiazepines act to increase inhibitory GABAergic transmission, an alternate approach to achieving the same end point might be to reduce excitatory glutamatergic neurotransmission.

Glutamate is the main excitatory neurotransmitter in the brain, acting through ionotropic and metabotropic (mGlu) receptor subtypes Monaghan et al., 1989, Conn and Pin, 1997. Based on sequence homology and pharmacology, the metabotropic receptors are divided into three classes: Group I metabotropic receptors include mGlu1 and mGlu5; Group II metabotropic receptors include mGlu2 and mGlu3; and Group III metabotropic receptors include mGlu4, mGlu6, mGlu7 and mGlu8 (Conn and Pin, 1997). Investigations into the therapeutic potential of targeting metabotropic receptors have been hampered by the lack of systemically active and selective compounds to test in animal models of diseases. However, recently, a series of compounds including SIB-1757, SIB-1893, and 2-methyl-6-(phenylethynyl)-pyridine (MPEP), were described as being highly selective noncompetitive antagonists at the mGlu5 receptor Varney et al., 1999, Gasparini et al., 1999. Subsequent studies, particularly with the systemically active antagonist MPEP, have allowed researchers to investigate the potential therapeutic effects of antagonizing mGlu5 receptors Spooren et al., 2000, Tatarczynska et al., 2001.

Studies in whole animals using MPEP suggest that antagonists of mGlu5 receptors may be useful in the treatment of anxiety Spooren et al., 2000, Tatarczynska et al., 2001. These published studies have examined the in vivo effects of MPEP in a variety of models of anxiety in both rats (social exploration, elevated plus maze, Geller–Seifter, fear-potentiated startle (FPS), and the conflict drinking test) and mice (stress-induced hyperthermia, marble burying, and the four-plate test) and reported qualitatively similar results to those seen with typical benzodiazepine anxiolytics (for review, see Spooren et al., 2001). However, a systematic comparison of the potency and efficacy of MPEP with a typical and an atypical anxiolytic in conditioned models of anxiety has not yet been reported. In order to evaluate the relative potency and efficacy as well as the potential use of mGlu5 receptor antagonists for the treatment of anxiety, we compared the effects of MPEP with two compounds used clinically to treat anxiety: buspirone (Rickels, 1987), a 5HT-1A partial agonist, and diazepam (Shader and Greenblatt, 1993), a GABA-A potentiator, in three models of conditioned anxiety in rats.