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Glutamate and Depression
Clinical and Preclinical Studies
IAN A. PAULa AND
PHIL SKOLNICKb
aLaboratory of Neurobehavioral Pharmacology and Immunology, Division of Neurobiology and Behavior Research, Departments of Psychiatry and Pharmacology, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
bDOV Pharmaceuticals, 433 Hackensack Avenue, Hackensack, New Jersey 07601, USA
Address for correspondence: Ian A. Paul, Ph.D., Department of Psychiatry and Human Behavior, Box 127, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216. Voice: 601-984-5883; fax: 601-984-5884.
ipaul{at}psychiatry.umsmed.edu
Ann. N.Y. Acad. Sci. 1003: 250-272 (2003).
The past decade has seen a steady accumulation of evidence supporting a role for the excitatory amino acid (EAA) neurotransmitter, glutamate, and its receptors in depression and antidepressant activity. To date, evidence has emerged indicating that N-methyl-d-aspartate (NMDA) receptor antagonists, group I metabotropic glutamate receptor (mGluR 1 and mGluR 5) antagonists, as well as positive modulators of  -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have antidepressant-like activity in a variety of preclinical models. Moreover, antidepressant-like activity can be produced not only by drugs modulating the glutamatergic synapse, but also by agents that affect subcellular signaling systems linked to EAA receptors (e.g., nitric oxide synthase). In view of the extensive colocalization of EAA and monoamine markers in nuclei such as the locus coeruleus and dorsal raphe, it is likely that an intimate relationship exists between regulation of monoaminergic and EAA neurotransmission and antidepressant effects. Further, there is also evidence implicating disturbances in glutamate metabolism, NMDA, and mGluR 1,5 receptors in depression and suicidality. Finally, recent data indicate that a single intravenous dose of an NMDA receptor antagonist is sufficient to produce sustained relief from depressive symptoms. Taken together with the proposed role of neurotrophic factors in the neuroplastic responses to stressors and antidepressant treatments, these findings represent exciting and novel avenues to both understand depressive symptomatology and develop more effective antidepressants.
Key Words: excitatory amino acid transmitter • NMDA receptor • AMPA receptor • metabotropic glutamate receptor • nitric oxide synthase • neuroplastic responses • antidepressant treatment
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