Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents

Abstract

Several lines of evidence implicate dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. Previous behavioral studies have indicated that metabotropic glutamate (mGlu) receptors may be useful targets for the treatment of psychosis. It has been shown that agonists and positive allosteric modulators of group II mGlu receptors produce potential antipsychotic effects in behavioral models of schizophrenia in rodents. Group III mGlu receptors seem to be also promising targets for a variety of neuropsychiatric and neurodegenerative disorders. However, despite encouraging data in animal models, most ligands of group III mGlu receptors still suffer from weak affinities, incapacity to cross the blood–brain barrier or absence of full pharmacological characterization. These limitations slow down the validation process of group III mGlu receptors as therapeutic targets. In this work, we choose to study an agonist of group III mGlu receptors (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) using intraperitoneal administration in three animal behavioral models predictive of psychosis or hallucinations. The results of the present study show that ACPT-I, given at doses of 10 or 30 mg/kg, decreased MK-801-induced hyperlocomotion and at a dose of 100 mg/kg decreased amphetamine-induced hyperlocomotion in rats. Furthermore, ACPT-I dose-dependently decreased DOI-induced head twitches in mice and suppresses DOI-induced frequency and amplitude of spontaneous EPSPs in slices from mouse brain frontal cortices. These data demonstrate that ACPT-I is a brain-penetrating compound and illustrates its promising therapeutic role for the treatment of schizophrenia.

Introduction

Several lines of evidence implicate dysfunction of glutamatergic system in the pathophysiology of schizophrenia, including post-mortem data showing changes in schizophrenic brains, which possibly arise from abnormal glutamatergic neurotransmission (Harrison, 1999), behavioral data indicating a psychotic-like action of NMDA receptor antagonists (e.g. phencyclidine (PCP), dizocilpine (MK-801)) in animals and humans (e.g. Krystal et al., 2003), and cognitive abnormalities produced by NMDA receptor antagonists, similar to those observed in schizophrenic patients (Moghaddam, 2004). Since decreased activation of NMDA receptor may result in psychotic symptoms, positive modulation of NMDA receptor became to be considered as a possible strategy for the treatment of schizophrenia. Indeed, a pharmacological enhancement of NMDA receptor function has been shown to induce positive therapeutic effects in clinical trials (Coyle et al., 2002).

The discovery of mGlu receptors has led to proposals that these modulatory glutamate receptors might be a target for psychotropic (i.e. antidepressant, anxiolytic and antipsychotic drugs) (Moghaddam, 2004, Palucha and Pilc, 2007). Group II and III mGlu receptors have mainly presynaptic localization (Schoepp, 2001) and serve as autoreceptors at brain structures (Gereau and Conn, 1995, Manzoni and Bockaert, 1995, Ugolini and Bordi, 1995, Cartmell and Schoepp, 2000). Their activation at glutamatergic nerve terminals was shown to cause a decrease in glutamate release, resulting in a functional antagonist of the glutamatergic system (Lovinger and McCool, 1995, Manzoni et al., 1995).

Behavioral studies indicated that selective agonists and positive modulators of group II mGlu receptors induce antipsychotic-like effects in rodents (Galici et al., 2005, Galici et al., 2006, Cartmell et al., 1999, Benneyworth et al., 2007). Moreover, a recent clinical study of Patil et al. (2007) showed that LY2140023, a prodrug of the selective group II mGlu receptor agonist LY404039, produced significant improvements in both positive and negative symptoms of schizophrenia compared to placebo, in a double-blind, placebo-controlled trial. Thus, activation of presynaptic mGlu receptors seems to be a possible strategy for the treatment of schizophrenia.

Similarly to mGlu2/3 receptors, group III mGlu receptors are highly expressed in the cerebral cortex and limbic areas of the brain and their activation inhibits glutamate release via presynaptical mechanism (Cartmell and Schoepp, 2000, Schoepp, 2001), however, they have been less studied, mainly due to the lack of high-affinity, highly selective and brain-penetrating agents. Recent studies showed that ACPT-I, a selective group III mGlu receptor agonist (Goudet et al., 2008), induced behavioral effects in animal models of anxiety, Parkinson's disease and pain (Pałucha et al., 2004, Goudet, 2008, Konieczny et al., 2007). However, this drug was never investigated after peripheral administration. In the present study we used ACPT-I to evaluate influence of group III mGlu receptor activation in rat and mouse models previously used to evaluate antipsychotic effects of group II mGlu receptor agonists (e.g. see Gewirtz and Marek, 2000, Rorick-Kehn et al., 2007). We used amphetamine and MK-801-induced hyperactivity models (Andine et al., 1999, Geyer and Ellenbroek, 2003) and (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitches (Gewirtz and Marek, 2000) with predictive validity of psychosis or hallucinations. Electrophysiological studies with cortical slices demonstrated that serotonin, as well as hallucinogen ((±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)), induces a robust increase in spontaneous EPSPs in layer V pyramidal neurons (Aghajanian and Marek, 2000). Therefore, we performed electrophysiological studies on the effect of ACPT-I on DOI-induced EPSPs slices from mouse brain frontal cortices. Results show that ACPT-I induces potential antipsychotic effects in all used behavioral models and that it suppresses DOI-induced frequency and amplitude of spontaneous EPSPs in slices from mouse brain frontal cortices. These data suggest that group III mGlu receptors constitute promising targets for the treatment of schizophrenia.