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Science 18 December 1998:
Vol. 282. no. 5397, pp. 2272 - 2275
DOI: 10.1126/science.282.5397.2272
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Reports

Regulation of Cocaine Reward by CREB

William A. Carlezon Jr., Johannes Thome, Valerie G. Olson, Sarah B. Lane-Ladd, Edward S. Brodkin, Noboru Hiroi, Ronald S. Duman, Rachael L. Neve, Eric J. Nestler *

Cocaine regulates the transcription factor CREB (adenosine 3',5'-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction. Overexpression of CREB in this region decreases the rewarding effects of cocaine and makes low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increases the rewarding effects of cocaine. Altered transcription of dynorphin likely contributes to these effects: Its expression is increased by overexpression of CREB and decreased by overexpression of mutant CREB. Moreover, blockade of kappa  opioid receptors (on which dynorphin acts) antagonizes the negative effect of CREB on cocaine reward. These results identify an intracellular cascade--culminating in gene expression--through which exposure to cocaine modifies subsequent responsiveness to the drug.

W. A. Carlezon Jr., J. Thome, V. G. Olson, S. B. Lane-Ladd, E. S. Brodkin, N. Hiroi, R. S. Duman, E. J. Nestler, Division of Molecular Psychiatry, Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06508, USA. R. L. Neve, Department of Genetics, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02178, USA.
*   To whom correspondence should be addressed.

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kappa -Opioid Tolerance and Dependence in Cultures of Dopaminergic Midbrain Neurons.
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