Targeting glutamate synapses in schizophrenia

Trends Mol Med. 2011 Dec;17(12):689-98. doi: 10.1016/j.molmed.2011.08.004. Epub 2011 Sep 28.

Abstract

Although early clinical observations implicated dopamine dysfunction in the neuropathology of schizophrenia, accumulating evidence suggests that multiple neurotransmitter pathways are dysregulated. The psychotomimetic actions of NMDA receptor antagonists point to an imbalance of glutamatergic signaling. Encouragingly, numerous preclinical and clinical studies have elucidated several potential targets for increasing NMDA receptor function and equilibrating glutamatergic tone, including the metabotropic glutamate receptors 2, 3 and 5, the muscarinic acetylcholine receptors M(1) and M(4), and the glycine transporter GlyT1. Highly specific allosteric and orthosteric ligands have been developed that modify the activity of these novel target proteins, and in this review we summarize both the glutamatergic mechanisms and the novel compounds that are increasing the promise for a multifaceted pharmacological approach to treat schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Antipsychotic Agents / administration & dosage*
  • Antipsychotic Agents / chemical synthesis
  • Antipsychotic Agents / therapeutic use
  • Excitatory Amino Acid Agonists / administration & dosage*
  • Excitatory Amino Acid Agonists / chemical synthesis
  • Excitatory Amino Acid Agonists / therapeutic use
  • Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Glycine Plasma Membrane Transport Proteins / metabolism
  • Humans
  • Ligands
  • Mice
  • Mice, Knockout
  • Muscarinic Agonists / administration & dosage*
  • Muscarinic Agonists / chemical synthesis
  • Muscarinic Agonists / therapeutic use
  • Rats
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / metabolism
  • Receptors, Muscarinic / metabolism
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Schizophrenia / drug therapy*
  • Schizophrenia / metabolism
  • Schizophrenia / physiopathology
  • Synapses / drug effects*
  • Synapses / metabolism
  • Synaptic Transmission / drug effects*

Substances

  • Antipsychotic Agents
  • Excitatory Amino Acid Agonists
  • Glycine Plasma Membrane Transport Proteins
  • Ligands
  • Muscarinic Agonists
  • Receptors, Metabotropic Glutamate
  • Receptors, Muscarinic
  • Receptors, N-Methyl-D-Aspartate
  • SLC6A9 protein, human