Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia?

Curr Drug Targets CNS Neurol Disord. 2002 Apr;1(2):215-25. doi: 10.2174/1568007024606177.

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 reflected by excitatory post-synaptic potentials (EPSPs) induced by serotonin (5-HT) acting on 5HT(2A) 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.

Publication types

  • Review

MeSH terms

  • Animals
  • Drug Evaluation, Preclinical / methods
  • Excitatory Amino Acid Agonists / chemistry
  • Excitatory Amino Acid Agonists / metabolism
  • Excitatory Amino Acid Agonists / therapeutic use*
  • Humans
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / metabolism
  • Schizophrenia / drug therapy*
  • Schizophrenia / metabolism

Substances

  • Excitatory Amino Acid Agonists
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • metabotropic glutamate receptor 3