PMID- 21956446
OWN - NLM
STAT- MEDLINE
DCOM- 20120821
LR  - 20231106
IS  - 1740-634X (Electronic)
IS  - 0893-133X (Print)
IS  - 0893-133X (Linking)
VI  - 37
IP  - 1
DP  - 2012 Jan
TI  - From revolution to evolution: the glutamate hypothesis of schizophrenia and its 
      implication for treatment.
PG  - 4-15
LID - 10.1038/npp.2011.181 [doi]
AB  - Glutamate is the primary excitatory neurotransmitter in mammalian brain. 
      Disturbances in glutamate-mediated neurotransmission have been increasingly 
      documented in a range of neuropsychiatric disorders including schizophrenia, 
      substance abuse, mood disorders, Alzheimer's disease, and autism-spectrum 
      disorders. Glutamatergic theories of schizophrenia are based on the ability of 
      N-methyl-D-aspartate receptor (NMDAR) antagonists to induce schizophrenia-like 
      symptoms, as well as emergent literature documenting disturbances of 
      NMDAR-related gene expression and metabolic pathways in schizophrenia. Research 
      over the past two decades has highlighted promising new targets for drug 
      development based on potential pre- and postsynaptic, and glial mechanisms 
      leading to NMDAR dysfunction. Reduced NMDAR activity on inhibitory neurons leads 
      to disinhibition of glutamate neurons increasing synaptic activity of glutamate, 
      especially in the prefrontal cortex. Based on this mechanism, normalizing excess 
      glutamate levels by metabotropic glutamate group 2/3 receptor agonists has led to 
      potential identification of the first non-monoaminergic target with comparable 
      efficacy as conventional antipsychotic drugs for treating positive and negative 
      symptoms of schizophrenia. In addition, NMDAR has intrinsic modulatory sites that 
      are active targets for drug development, several of which show promise in 
      preclinical/early clinical trials targeting both symptoms and cognition. To date, 
      most studies have been done with orthosteric agonists and/or antagonists at 
      specific sites. However, allosteric modulators, both positive and negative, may 
      offer superior efficacy with less danger of downregulation.
FAU - Moghaddam, Bita
AU  - Moghaddam B
AD  - Department of Neuroscience and Psychiatry, University of Pittsburgh, Pittsburgh, 
      PA 15260, USA. bita@pitt.edu
FAU - Javitt, Daniel
AU  - Javitt D
LA  - eng
GR  - R01 DA003383/DA/NIDA NIH HHS/United States
GR  - R01DA03383/DA/NIDA NIH HHS/United States
GR  - R01 MH084906/MH/NIMH NIH HHS/United States
GR  - R56 MH084906/MH/NIMH NIH HHS/United States
GR  - R01 MH048404/MH/NIMH NIH HHS/United States
GR  - R37 MH48404/MH/NIMH NIH HHS/United States
GR  - R37 MH048404/MH/NIMH NIH HHS/United States
GR  - P50 MH086385/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20110928
PL  - England
TA  - Neuropsychopharmacology
JT  - Neuropsychopharmacology : official publication of the American College of 
      Neuropsychopharmacology
JID - 8904907
RN  - 0 (Neurotransmitter Agents)
RN  - 0 (Psychotropic Drugs)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3KX376GY7L (Glutamic Acid)
SB  - IM
MH  - Glutamic Acid/*physiology
MH  - Humans
MH  - Neurotransmitter Agents/*physiology
MH  - Psychotropic Drugs/*therapeutic use
MH  - Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors/physiology
MH  - Schizophrenia/*drug therapy/*metabolism/physiopathology
PMC - PMC3238069
EDAT- 2011/10/01 06:00
MHDA- 2012/08/22 06:00
PMCR- 2013/01/01
CRDT- 2011/09/30 06:00
PHST- 2011/09/30 06:00 [entrez]
PHST- 2011/10/01 06:00 [pubmed]
PHST- 2012/08/22 06:00 [medline]
PHST- 2013/01/01 00:00 [pmc-release]
AID - npp2011181 [pii]
AID - 10.1038/npp.2011.181 [doi]
PST - ppublish
SO  - Neuropsychopharmacology. 2012 Jan;37(1):4-15. doi: 10.1038/npp.2011.181. Epub 
      2011 Sep 28.