Journal
TRENDS IN MOLECULAR MEDICINE
Volume 17, Issue 12, Pages 689-698Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.molmed.2011.08.004
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Funding
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke,
- National Institute of Health-supported Molecular Library Program Center Network
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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.
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