Recent compelling evidence has suggested that the glutamate system is a primary mediator
of psychiatric pathology and also a target for rapid-acting antidepressants. Clinical
research in mood and anxiety disorders has shown alterations in levels, clearance,
and metabolism of glutamate and consistent volumetric changes in brain areas where
glutamate neurons predominate. In parallel, preclinical studies with rodent stress
and depression models have found dendritic remodeling and synaptic spines reduction
in corresponding areas, suggesting these as major factors in psychopathology. Enhancement
of glutamate release/transmission, in turn induced by stress/glucocorticoids, seems
crucial for structural/functional changes. Understanding mechanisms of maladaptive
plasticity may allow identification of new targets for drugs and therapies. Interestingly,
traditional monoaminergic-based antidepressants have been repeatedly shown to interfere
with glutamate system function, starting with modulation of N-methyl-D-aspartate (NMDA) receptors. Subsequently, it has been shown that antidepressants
reduce glutamate release and synaptic transmission; in particular, it was found antidepressants
prevent the acute stress-induced enhancement of glutamate release. Additional studies
have shown that antidepressants may partly reverse the maladaptive changes in synapses/circuitry
in stress and depression models. Finally, a number of studies over the years have
shown that these drugs regulate glutamate receptors, reducing the function of NMDA
receptors, potentiating the function of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic
acid receptors, and, more recently, exerting variable effects on different subtypes
of metabotropic glutamate receptors. The development of NMDA receptor antagonists
has opened new avenues for glutamatergic, rapid acting, antidepressants, while additional
targets in the glutamate synapse await development of new compounds for better, faster
antidepressant action.
Key Words
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Article info
Publication history
Accepted:
November 13,
2012
Received in revised form:
November 13,
2012
Received:
July 25,
2012
Footnotes
Authors LM and GT contributed equally to this work.
Identification
Copyright
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