Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview

Pharmacological Reviews
Daniela TarditoMaurizio Popoli

Abstract

Regulation of gene expression represents a major component in antidepressant drug action. The effect of antidepressant treatments on the function of cAMP-responsive element binding protein (CREB), a transcription factor that regulates expression of several genes involved in neuroplasticity, cell survival, and cognition, has been extensively studied. Although there is general agreement that chronic antidepressants stimulate CREB function, conflicting results suggest that different effects may depend on drug type, drug dosage, and different experimental paradigms. CREB function is activated by a vast array of physiological stimuli, conveyed through a number of signaling pathways acting in concert, but thus far the effects of antidepressants on CREB have been analyzed mostly with regard to the cAMP-protein kinase A pathway. A growing body of data shows that other major pathways, such as the calcium/calmodulin-dependent kinase and the mitogen-activated kinase cascades, are involved in activity-dependent regulation of gene expression and may also be implicated in the mechanism of action of antidepressants. In this article the available evidence is reviewed with an attempt to identify the reasons for experimental discrepancies and po...Continue Reading

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