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Anxiolytic-like activity of MGS0039, a potent group II metabotropic glutamate receptor antagonist, in a marble-burying behavior test

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Abstract

Glutamatergic abnormalities are involved in several psychiatric disorders. Clinical evidence demonstrates altered glutamatergic neurotransmission in patients suffering from obsessive-compulsive disorder. MGS0039, (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, is a novel group II metabotropic glutamate (mGlu) receptor antagonist. We examined MGS0039's potential anti-obsessive-compulsive disorder activity, using the marble-burying behavior test as a model of obsessive-compulsive disorder. MGS0039 as well as LY341495 ((2S,1′S,2′S)-2-(9-xanthylmethyl)-2-(2′-carboxycycloprolyl)glycine), another group II mGlu receptor antagonist, inhibited marble-burying behavior. We also demonstrated that this effect was significantly attenuated by a group II mGlu receptor agonist. This data indicates that group II mGlu receptor antagonists may exert anti-obsessive-compulsive disorder effects in clinical use.

Introduction

It is now well recognized that glutamate is the principal excitatory neurotransmitter in the central nervous system. Animal models and human clinical data clearly show that glutamatergic neurotransmission is potentially involved in a very wide range of central nervous system disorders, including epilepsy, neurodegenerative diseases, stroke, traumatic brain injury, pain, psychiatric diseases (Danysz et al., 1995, Meldrum, 2000). At present, abnormalities of glutamatergic neurotransmission have been observed in several psychiatric disorders such as schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, major depression and obsessive-compulsive disorder (Clinton et al., 2003, Carlsson, 2001, McCullumsmith and Meador-Woodruff, 2002, Rosenberg et al., 2000).

Obsessive-compulsive disorder is characterized by repeated, persistent and dysphoric thoughts (obsessions), which are ego-dystonic, repetitive, seemingly purposeful behaviors (compulsions) (Rasmussen and Eisen, 1992). Although obsessive-compulsive disorder is grouped as an anxiety disorder, benzodiazepines, clinically effective anxiolytic drugs, are generally ineffective in relieving obsessive-compulsive disorder symptoms. To date, the most efficacious treatments for obsessive-compulsive disorder are anti-depressants, including clomipramine and selective serotonin reuptake inhibitors (SSRIs) (Boyer et al., 1991).

Some clinical evidence indicates that glutamatergic abnormalities are associated with obsessive-compulsive disorder symptoms. Brain imaging studies of obsessive-compulsive disorder patients have demonstrated a reversible glutamatergically mediated thalamo-cortical-striatal dysfunction (Rosenberg et al., 2001). Moreover, using proton magnetic resonance spectroscopy, it is clear that abnormal glutamatergic neurotransmissions were observed in the caudate of obsessive-compulsive disorder patients (Rosenberg et al., 2000). Therefore, regulating glutamatergic neurotransmission may result in effective therapy for obsessive-compulsive disorder patients.

Glutamate mediates its effects via two types of receptors: ionotropic receptors and metabotropic receptors (Monaghan et al., 1989, Conn and Pin, 1997). At present, eight subtypes of mGlu receptors have been cloned (Conn and Pin, 1997). Based on the expression pattern of distinct mGlu receptors in the central nerve system, agonists or antagonists of mGlu receptors are believed to offer the potential for new therapeutic agents for a number of neurological and psychiatric disorders (Knopfel et al., 1995, Conn and Pin, 1997, Nicoletti et al., 1997). MGlu receptors are classified into three subgroups (groups I–III). Group II mGlu receptors are mainly localized in presynapses and serve an important role in regulating glutamatergic neurotransmission (Cartmell and Schoepp, 2000).

MGS0039, (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, is a novel and potent antagonist of group II mGlu receptor and exhibits antidepressant-like activity (Chaki et al., 2004). In the present study, we examined whether glutamatergic change induced by MGS0039 resulted in anti-obsessive-compulsive disorder activity in the marble-burying behavior test. The marble-burying behavior test has been suggested as a useful model for evaluating anti-obsessive-compulsive disorder drugs, because no change in the intensity of the marble-burying behavior occurred during repeated testing (this is considered as compulsive behavior) and because SSRIs, which have been found effective in treating symptoms of clinical obsessive-compulsive disorder, antagonize this burying behavior (Njung'e and Handley, 1991a, Njung'e and Handley, 1991b).

Section snippets

Materials and methods

Male ICR mice (25–35 g, Charles River, Yokohama, Japan) were used. Mice were housed in groups of 10 until the experiments begun. Living cages for group housing were measured 24×35×15 cm. Mice were maintained under a 12 h light/dark cycle (lights on 7:00 AM). Temperature was held constant at 23 °C with a relative humidity of 50%. Food and water were made available ad libitum.

MGS0039, LY341495 ((2S,1′S,2′S)-2-(9-xanthylmethyl)-2-(2′-carboxycycloprolyl)glycine), LY354740 ((1S,2S,5R,6S

Results

Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), significantly blocked marble-burying activity at doses of 10 and 30 mg/kg [F(3,36)=8.40, P<0.01] (Fig. 1). Mice treated with MGS0039, a potent and selective antagonist of group II mGlu receptor, reduced marble-burying in a significant and dose-dependent manner at doses of 3 and 10 mg/kg [F(3,36)=5.32, P<0.01] (Fig. 1). No significant change was observed in spontaneous locomotor activity in MGS0039 treated mice (counts/30 min vehicle,

Discussion

In the previous study, we demonstrated that MGS0039 showed high affinity and selectivity for group II mGlu receptor and no affinity for serotonergic and noradrenergic receptors and transporters even at 10 μM (Chaki et al., 2004).

In the present study, we obtained the results that MGS0039 as well as fluvoxamine showed anxiolytic-like effect in the marble-burying behavioral test, which is considered a model for obsessive-compulsive disorder (Njung'e and Handley, 1991a), without affecting

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