Preclinical Pharmacology of mGlu2 / 3 Receptor Agonists: Novel Agents for Schizophrenia?

Darryle   D.   Schoepp; Gerard   J.   Marek

Abstract

Agonists for mGlu2 / 3 receptors decrease the evoked release of glutamate at certain (ie. forebrain / limbic) glutamatergic synapses, indicating that the functional role of mGlu2 and / or mGlu3 receptors is to suppress glutamate excitations. This offers a mechanism for dampening glutamate excitation under pathological states resulting from excessive glutamate release. Based, in part, on the psychotomimetic actions of phencyclidine (PCP)- like drugs, excessive or pathological glutamate release has been implicated in a number of clinical conditions including psychosis. With this in mind, the pharmacology of multiple mGlu2 / 3 receptor agonists have been investigated in PCP treated rats. Agonists for mGlu2 / 3 receptors such as LY354740 and LY379268 have been shown to block certain behavioral responses to PCP in rats. The effects of mGlu2 / 3 agonists on PCP-induced behaviors are blocked by a low doses of a selective mGlu2 / 3 receptor antagonist, indicating that these actions are mediated via mGlu2 / 3 receptors. In addition, mGlu2 / 3 agonists potently suppress glutamate release in rat prefrontal cortex, as relfected by excitatory post-synaptic potentials (EPSPs) induced by serotonin (5-HT) acting on 5HT2A receptors. These actions of LY354740 and LY379268 are also blocked by a selective mGlu2 / 3 antagonist. Atypical antipsychotic drugs such as clozapine also suppress 5-HT-induced EPSPs in this brain region, thus suggesting a common pathway for the actions of atypical antipsychotic drugs and mGlu2 / 3 receptor agonists. As glutamatergic dysfunction has been implicated in psychotic states and possibly in the etiology of schizophrenia, clinical studies with mGlu2 / 3 agonists may be warranted to further explore the validity of the glutamatergic hypothesis of schizophrenia.

Keywords: mglu2/3 receptor agonists, phencyclidine, schizophrenia, psychosis, metabotropic glutamate receptors, excitatory amino acid, antipsychotics

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