CRF–CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats
- Olivier George*,†,
- Sandy Ghozland*,
- Marc R. Azar*,
- Pietro Cottone*,
- Eric P. Zorrilla*,
- Loren H. Parsons*,
- Laura E. O'Dell‡,
- Heather N. Richardson*, and
- George F. Koob*
- *Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037; and
- ‡Department of Psychology, University of Texas, El Paso, TX 79968
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Communicated by Floyd E. Bloom, The Scripps Research Institute, La Jolla, CA, August 13, 2007 (received for review May 1, 2007)
Abstract
Nicotine, the main psychoactive ingredient of tobacco, induces negative emotional symptoms during abstinence that contribute to a profound craving for nicotine. However, the neurobiological mechanisms underlying how nicotine produces dependence remains poorly understood. We demonstrate one mechanism for both the anxiety-like symptoms of withdrawal and excessive nicotine intake observed after abstinence, through recruitment of the extrahypothalamic stress peptide corticotropin-releasing factor (CRF) system and activation of CRF1 receptors. Overactivation of the CRF–CRF1 system may contribute to nicotine dependence and may represent a prominent target for investigating the vulnerability to tobacco addiction.
Footnotes
- †To whom correspondence should be addressed. E-mail: ogeorge{at}scripps.edu
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Author contributions: O.G. and S.G. contributed equally to this work; O.G., S.G., P.C., E.P.Z., L.H.P., L.E.O., H.N.R., and G.F.K. designed research; O.G., S.G., M.R.A., P.C., E.P.Z., and L.H.P. performed research; O.G. and S.G. analyzed data; and O.G., S.G., and G.F.K. wrote the paper.
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The authors declare no conflict of interest.
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↵ § Richardson, H. N., Funk, C. K., Grant, Y., Zorrilla, E. P., Koob, G. F. (2006) Program No. 783 4 Neuroscience Meeting Planner, Atlanta, GA (Soc Neurosci, Washington, DC), www.sfn.org/am2006/.
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↵ ¶ Specio, S. E., Zorrilla, E. P., O'Dell, L. E., Boutrel, B., Smith, R. T., Grant, Y., Koob, G. F. (2004) Program No. 77711 Neuroscience Meeting Planner (Soc Neurosci, Washington, DC), http://sfn.scholarone.com/itin2004/.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0707585104/DC1.
- Abbreviations:
- CRF,
- corticotropin-releasing factor;
- MPZP,
- (N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5α]pyrimidin-7-amine;
- CRF-L-IR,
- CRF-like-immunoreactivity.
- © 2007 by The National Academy of Sciences of the USA
