Anxiolytic-like activity of the mGluR5 antagonist MPEP: A comparison with diazepam and buspirone
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.
Section snippets
Animals
Naı̈ve adult male Wistar rats (Charles River, 225–300 g) were used for FPS and ultrasonic vocalization (USV) studies. Animals were housed in groups of three under a 12-h light/dark cycle (lights on 06:30 h). The animals had free access to food and water. Twenty-five individually housed adult male Sprague–Dawley rats (Harlan, 290–330 g) were used for the Geller–Seifter test. These animals were fed daily 2 h after the completion of the session to maintain them at 85% of their free-feeding body
Results
The effect of diazepam, buspirone, and MPEP on FPS is shown in Fig. 1A–C. In the FPS test, anxiety is indicated when the startle response in the light is greater than the startle response in the dark. A significant difference between the response in the vehicle group and the drug-treated group in the light suggests that the dose has produced an anxiolytic effect. Multivariate analysis using a two-way ANOVA and post hoc SNK test determined that 3 mg/kg diazepam significantly decreased startle
Discussion
Recent data suggest that the mGluR5 antagonist, MPEP, demonstrates anxiolytic activity in a number of animal models of anxiety. For example, Spooren et al. (2000) and Schulz et al. (2001) examined the effects of MPEP in a number of assays of conditioned and unconditioned anxiety. The present report confirms the anxiolytic-like activity of MPEP in the conditioned anxiety assays of the Geller–Seifter and FPS assays and extends those findings with anxiolytic-like activity in an assay of
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