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The Journal of Neuroscience, November 1, 2006, 26(44):11324-11332; doi:10.1523/JNEUROSCI.3096-06.2006

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Behavioral/Systems/Cognitive
Corticotropin-Releasing Factor within the Central Nucleus of the Amygdala Mediates Enhanced Ethanol Self-Administration in Withdrawn, Ethanol-Dependent Rats

Cindy K. Funk,¹ Laura E. O'Dell,² Elena F. Crawford,¹ and George F. Koob¹

¹The Scripps Research Institute, La Jolla, California 92037, and ²The University of Texas El Paso, El Paso, Texas 79968

Correspondence should be addressed to Dr. Cindy K. Funk, The Scripps Research Institute, 10550 North Torrey Pines Road, SP-30-2400, La Jolla, CA 92037. Email: creiter{at}scripps.edu

Alcohol dependence is characterized by excessive consumption, loss of control over intake, and the presence of a withdrawal syndrome, including both motivational and physical symptoms. The motivational symptoms, including anxiety, have been hypothesized to be important factors eliciting excessive drinking during abstinence. Previous work has shown that ethanol-dependent rats also display enhanced anxiety-like behaviors and enhanced ethanol self-administration during withdrawal, likely resulting from dysregulation of brain corticotropin-releasing factor (CRF) stress systems. The present study was designed to explore the brain sites within the extended amygdala [central nucleus of the amygdala (CeA), lateral bed nucleus of the stria terminalis (BNST), and nucleus accumbens shell (NAcSh)] that mediate the increased ethanol self-administration observed during withdrawal. Ethanol-dependent animals showed an increase in ethanol self-administration after acute withdrawal relative to nondependent controls. The CRF antagonist D-Phe-CRF_12–41 ([D-Phe¹²,Nle^21,38,C MeLeu³⁷]-rCRF_(12–41)) was administered into the CeA, lateral BNST, or NAcSh of acute-withdrawn dependent and nondependent rats. Administered into the CeA, the antagonist reduced ethanol self-administration in dependent animals, with no effect in nondependent animals. Administration of D-Phe-CRF_12–41 into the lateral BNST and NAcSh was without effect on ethanol self-administration in dependent and nondependent animals. At the same time point of withdrawal, there was a decrease in CRF immunoreactivity within the CeA, suggesting an increased extracellular release of CRF during withdrawal. There was no change in CRF immunoreactivity in the BNST or NAcSh. These results indicate that CRF, specifically within the CeA, plays a role in mediating excessive ethanol consumption in ethanol-dependent animals.

Key words: ethanol; central amygdala; self-administration; rat; CRF; lateral BNST; nucleus accumbens shell

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Received July 20, 2006; revised Sept. 1, 2006; accepted Sept. 21, 2006.

Correspondence should be addressed to Dr. Cindy K. Funk, The Scripps Research Institute, 10550 North Torrey Pines Road, SP-30-2400, La Jolla, CA 92037. Email: creiter{at}scripps.edu

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