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PNAS 105 (23): 8114-8119

Copyright © 2008 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / NEUROSCIENCE

GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse

Sebastien Carnicella*, Viktor Kharazia*, Jerome Jeanblanc*, Patricia H. Janak*,{dagger}, and Dorit Ron*,{dagger},{ddagger}

*The Ernest Gallo Research Center and {dagger}Department of Neurology, University of California at San Francisco, Emeryville, CA 94608

Edited by Hans Thoenen, Max Planck Institute of Neurobiology, Martinsried, Germany, and approved April 23, 2008

Received for publication December 13, 2007.

Abstract: Previously, we demonstrated that the action of the natural alkaloid, ibogaine, to reduce alcohol (ethanol) consumption is mediated by the glial cell line-derived neurotrophic factor (GDNF) in the ventral tegmental area (VTA). Here we set out to test the actions of GDNF in the VTA on ethanol-drinking behaviors. We found that GDNF infusion very rapidly and dose-dependently reduced rat ethanol, but not sucrose, operant self-administration. A GDNF-mediated decrease in ethanol consumption was also observed in rats with a history of high voluntary ethanol intake. We found that the action of GDNF on ethanol consumption was specific to the VTA as infusion of the growth factor into the neighboring substantia nigra did not affect operant responses for ethanol. We further show that intra-VTA GDNF administration rapidly activated the MAPK signaling pathway in the VTA and that inhibition of the MAPK pathway in the VTA blocked the reduction of ethanol self-administration by GDNF. Importantly, we demonstrate that GDNF infused into the VTA alters rats' responses in a model of relapse. Specifically, GDNF application blocked reacquisition of ethanol self-administration after extinction. Together, these results suggest that GDNF, via activation of the MAPK pathway, is a fast-acting selective agent to reduce the motivation to consume and seek alcohol.

Key Words: addiction • growth factor • self-administration

Freely available online through the PNAS open access option.

Author contributions: S.C., P.H.J., and D.R. designed research; S.C., V.K., and J.J. performed research; S.C. and P.H.J. analyzed data; and S.C. and D.R. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0711755105/DCSupplemental.

{ddagger}To whom correspondence should be addressed at: 5858 Horton Street, Suite 200, Emeryville, CA 94608. E-mail: dorit.ron{at}ucsf.edu

© 2008 by The National Academy of Sciences of the USA

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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