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PNAS 104 (11): 4647-4652

Copyright © 2007 by the National Academy of Sciences.


VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants

Jennifer L. Warner-Schmidt Ronald S. Duman*

Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, CT 06508

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved January 19, 2007

Received for publication November 20, 2006.

Abstract: The neural mechanisms underlying the cellular and behavioral responses to antidepressants are not yet known. Up-regulation of growth factors and adult neurogenesis suggest a role for one or more of these factors in the action of antidepressants. One candidate of interest is vascular endothelial growth factor (VEGF), which was initially characterized for its role in angiogenesis, but also exerts direct mitogenic effects on neural progenitors in vitro. Results of this study demonstrate that VEGF is induced by multiple classes of antidepressants at time points consistent with the induction of cell proliferation and therapeutic action of these treatments. We find that VEGF signaling through the Flk-1 receptor is required for antidepressant-induced cell proliferation. We also show that VEGF-Flk-1 signaling is required and sufficient for behavioral responses in two chronic and two subchronic antidepressant models. Taken together, these studies identify VEGF and VEGF-Flk-1 signaling as mediators of antidepressant actions and potential targets for therapeutic intervention.

Key Words: desipramine • electroconvulsive shock • endothelial cells • fluoxetine • neurogenesis

Author contributions: J.L.W.-S., and R.S.D. designed research; J.L.W.-S. performed research; J.L.W.-S. analyzed data; and J.L.W.-S. and R.S.D. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS direct submission.

This article contains supporting information online at

*To whom correspondence should be addressed at: 34 Park Street, New Haven, CT 06508. E-mail: ronald.duman{at}

© 2007 by The National Academy of Sciences of the USA

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