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The Journal of Neuroscience, December 20, 2006, 26(51):13287-13296; doi:10.1523/JNEUROSCI.3795-06.2006

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Cellular/Molecular
c-Fos Facilitates the Acquisition and Extinction of Cocaine-Induced Persistent Changes

Jianhua Zhang,¹ Lu Zhang,² Hongyuan Jiao,² Qi Zhang,² Dongsheng Zhang,² Danwen Lou,² Jonathan L. Katz,³ and Ming Xu²

¹Division of Neuropathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, ²Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois 60637, and ³Medications Discovery Research Branch, National Institute on Drug Abuse, Baltimore, Maryland 21224

Correspondence should be addressed to Dr. Ming Xu, Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637. Email: mxu{at}dacc.uchicago.edu

Development of drug addiction involves persistent neurobiological changes. The dopamine D₁ receptor is involved in mediating cocaine-induced neuroadaptation, yet the underlying intracellular mechanisms remain unclear. We examined a potential role of the immediate early gene Fos, which is robustly and rapidly induced by cocaine via D₁ receptors, in mediating cocaine-induced persistent neurobiological changes by creating and analyzing a mouse in which Fos is primarily disrupted in D₁ receptor-expressing neurons in the brain. We show that the expression levels of several transcription factors, neurotransmitter receptors, and intracellular signaling molecules induced by repeated cocaine administration are altered in Fos-deficient brains. Dendritic remodeling of medium spiny neurons induced by repeated exposure to cocaine is blunted in the mutant mice. The mutant mice exhibit attenuated behavioral sensitization after repeated exposure to cocaine and more persistent memory of cocaine-induced conditioned place preference. Our findings indicate that c-Fos produced in D₁ receptor-expressing neurons integrates mechanisms to facilitate both the acquisition and extinction of cocaine-induced persistent changes.

Key words: cocaine; dopamine D₁ receptors; signal transduction; c-Fos; gene expression; dendritic morphology; behaviors

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Received March 8, 2005; revised Nov. 12, 2006; accepted Nov. 13, 2006.

Correspondence should be addressed to Dr. Ming Xu, Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637. Email: mxu{at}dacc.uchicago.edu

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