Glutamate as a therapeutic target in psychiatric disorders.
Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD.
Javitt
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Program in Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute for Psychiatric Research/New York University School of Medicine, Orangeburg, NY 10962, USA. javitt@nki.rfmh.org
D000818:Animals; D004195:Disease Models, Animal; D015195:Drug Design; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy*; D010622:Phencyclidine; D017470:Receptors, Glutamate / Q000145:classification; D018009:Receptors, Glycine / Q000819:agonists / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D010622:Phencyclidine