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J. Biol. Chem., Vol. 283, Issue 5, 2751-2760, February 1, 2008

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CREB Modulates the Functional Output of Nucleus Accumbens Neurons

A CRITICAL ROLE OF N-METHYL-D-ASPARTATE GLUTAMATE RECEPTOR (NMDAR) RECEPTORS^*

Yanhua H. Huang, Ying Lin¹, Travis E. Brown¹, Ming-Hu Han^¶1, Daniel B. Saal, Rachael L. Neve^||, R. Suzanne Zukin, Barbara A. Sorg, Eric J. Nestler^¶, Robert C. Malenka^**, and Yan Dong^**2

From the Program in Neuroscience, Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Wegner 205, Pullman, Washington 99164, the Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, the ^||Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478, the ^¶Departments of Psychiatry and Basic Neuroscience, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9070, and the ^**Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, California 94304

Nucleus accumbens (NAc) medium spiny neurons cycle between two states, a functionally inactive downstate and a functionally active upstate. Here, we show that activation of the transcription factor cAMP-response element-binding protein (CREB), a common molecular response to several drugs of abuse, increases both duration of the upstate and action potential firing during the upstate. This effect of CREB is mediated by enhanced N-methyl-D-aspartate glutamate receptor (NMDAR) function: increased CREB activity increases both NMDAR-mediated synaptic currents and surface level of NMDARs, while inhibition of NMDARs abolishes the effect of CREB on upstate duration. Furthermore, mimicking the effect of CREB by pharmacological enhancement of NMDAR function in the NAc in vivo suppressed novelty- and cocaine-elicited locomotor activity. These findings suggest that by enhancing NMDAR-mediated synaptic transmission, CREB activation promotes the proportion of time NAc neurons spend in the upstate. This effect, along with the CREB enhancement of NAc membrane excitability (Dong, Y., Green, T., Saal, D., Marie, H., Neve, R., Nestler, E. J., and Malenka, R. C. (2006) Nat. Neurosci. 9, 475–477), may counteract drug-induced maladaptations in the NAc and thus ameliorate the addictive state.

Received for publication, August 8, 2007 , and in revised form, October 23, 2007.

^* This work was supported in part by the Program of Alcohol and Drug Abuse Research Program at Washington State University (to Y. D. and B. A. S.), NARSAD (to Y. H. H. and M. M. H.), and the National Institutes of Health (to R. L. N., R. S. Z., B. A. S., E. J. N., R. C. M., and Y. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: WA State University, P. O. Box 646520-VCAPP, Pullman, WA 99164. Tel.: 509-335-5960; Fax: 509-335-4650; E-mail: yandong{at}vetmed.wsu.edu.

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