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The Journal of Neuroscience, August 15, 2000, 20(16):6210-6217

NAC-1 Is a Brain POZ/BTB Protein That Can Prevent Cocaine-Induced Sensitization in the Rat

Scott A. Mackler^{1, 2, 3, 4, 5}, Laxminarayana Korutla^{2, 4}, Xian-Yuan Cha^{1, 3}, Mark J. Koebbe^{2, 4}, Keith M. Fournier⁵, M. Scott Bowers⁶, and Peter W. Kalivas⁶

Departments of ¹ Medicine and ² Psychiatry, Philadelphia Veterans Administration Medical Center, and Departments of ³ Medicine, ⁴ Psychiatry, and ⁵ Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and ⁶ Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425

Levels of the mRNA NAC-1 are increased in the rat forebrain weeks after cocaine exposure. This long-term neuroadaptation occurs during the expression of behavioral sensitization, a model of psychostimulant-induced paranoia. NAC-1, the protein encoded by this cocaine-regulated mRNA, contains a Pox virus and zinc finger/bric-a-brac tramtrack broad complex (POZ/BTB) motif, which mediates interactions among several transcriptional regulators. The present studies demonstrate that NAC-1 acts as a transcription factor. NAC-1 was localized to the nucleus of neurons in the brain. Transfection of NAC-1 in cell culture repressed transcription of a reporter gene. NAC-1 was also able to affect the actions of other POZ/BTB proteins in mammalian two-hybrid studies; these interactions required the presence of the POZ/BTB domain. However, NAC-1 appears to be a unique POZ/BTB transcriptional regulator because it does not contain any zinc finger regions found in these other DNA-binding proteins. Adenoviral-mediated overexpression of NAC-1 protein in the rat nucleus accumbens prevented the development but not the expression of behavioral sensitization produced by repeated administration of cocaine. Thus, NAC-1 may modify the long-term behaviors of psychostimulant abuse by regulating gene transcription in the mammalian brain.

Key words: behavioral sensitization; cocaine; DNA; neuron; POZ protein; rat; transcription factor

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20166210-08$05.00/0

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