Fluoxetine and glutamate release and transmission

Dysfunction of the glutamate system has been associated with the pathophysiology of psychiatric disorders, including mood and anxiety disorders. Changes in levels and clearance of glutamate and its metabolites were found in cortical/limbic areas of depressed patients, while neuroimaging and histopathological studies showed morphological and functional alterations in the same brain areas. Preclinical studies on stress-based animal models of mood and anxiety disorders showed that stress potently affects glutamate synaptic transmission and plasticity and induces consistent dendritic remodeling and synaptic spines reduction in corresponding brain areas. Interestingly, chronic fluoxetine, as well as other traditional antidepressants, not only have been shown to modulate the glutamate system in basal conditions, but are also able to prevent the enhancement of glutamate release induced by acute stress and partly reverse the maladaptive changes in synapses and circuitry caused by exposure to chronic stress. Moreover, the chronic treatment with fluoxetine induces changes in the expression, regulation and function of glutamate receptors, reducing the activity of NMDA receptors, potentiating AMPA receptors, and modulating metabotropic glutamate receptors. These findings suggest that glutamate transmission may be a relevant target for the therapeutic action of antidepressants in general, and fluoxetine in particular. Understanding the action of traditional drugs on glutamate transmission could be of great help in developing new drugs directly targeted at the glutamate synapse.