Mechanism of action of antipsychotic drugs: from dopamine D(2) receptor antagonism to glutamate NMDA facilitation.
BACKGROUND
The fundamental pathologic processes associated with schizophrenia remain uncertain.


OBJECTIVE
The goal of this article was to review imaging evidence suggesting that schizophrenia is associated with excessive stimulation of D(2) receptors, as well as imaging experiments supporting the hypothesis that this dysregulation might be secondary to N- methyl-d-aspartate (NMDA) dysfunction.


CONCLUSIONS
Recent imaging data support the association of schizophrenia with a dopamine endophenotype involving excessive subcortical dopamine function. Animal and imaging data are consistent with the idea that this abnormality might be secondary to a synaptic disconnectivity involving the prefrontal cortex, which is well modeled by NMDA antagonist administration. In turn, this dopamine dysregulation might worsen synaptic connectivity and NMDA function. Thus, both glutamate/dopamine and dopamine/glutamate interactions may be relevant to schizophrenia pathophysiology and treatment. A deficit in glutamate transmission may lead to the dopamine endophenotype associated with this illness, and dopamine alterations in turn might exacerbate glutamate transmission deficits. The view that NMDA alterations are primary and dopamine alterations are secondary is probably oversimplistic, as both sets of abnormalities reinforce each other. A consequence of this general model is that direct intervention to support NMDA function might be beneficial as an augmentation strategy for the treatment of schizophrenia. Thus, it is proposed that schizophrenia is associated with strongly interconnected abnormalities of glutamate and dopamine transmission: NMDA hypofunction in the prefrontal cortex and its connections might generate a pattern of dysregulation of dopamine systems that, in turn, further weakens NMDA-mediated connectivity and plasticity.
Laruelle
Marc
M
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. ml393@columbia.edu
Frankle
W Gordon
WG
Narendran
Rajesh
R
Kegeles
Lawrence S
LS
Abi-Dargham
Anissa
A
D014150:Antipsychotic Agents / Q000494:pharmacology*; D004298:Dopamine / Q000502:physiology; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D018698:Glutamic Acid / Q000502:physiology; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D004298:Dopamine