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The Journal of Neuroscience, September 26, 2007, 27(39):10497-10507; doi:10.1523/JNEUROSCI.2566-07.2007

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Behavioral/Systems/Cognitive
FosB Induction in Orbitofrontal Cortex Mediates Tolerance to Cocaine-Induced Cognitive Dysfunction

Catharine A. Winstanley,¹ Quincey LaPlant,¹ David E. H. Theobald,¹ Thomas A. Green,¹ Ryan K. Bachtell,¹ Linda I. Perrotti,¹ Ralph J. DiLeone,¹ Scott J. Russo,¹ William J. Garth,² David W. Self,¹ and Eric J. Nestler¹

¹Departments of Psychiatry and Basic Neuroscience and ²Charles River Laboratories CSS, The University of Texas Southwestern Medical Center, Dallas, Texas 75390

Correspondence should be addressed to Eric J. Nestler, Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070. Email: eric.nestler{at}utsouthwestern.edu

Current cocaine users show little evidence of cognitive impairment and may perform better when using cocaine, yet withdrawal from prolonged cocaine use unmasks dramatic cognitive deficits. It has been suggested that such impairments arise in part through drug-induced dysfunction within the orbitofrontal cortex (OFC), yet the neurobiological mechanisms remain unknown. We observed that chronic cocaine self-administration increased expression of the transcription factor FosB within both medial and orbitofrontal regions of the rat prefrontal cortex. However, the increase in OFC FosB levels was more pronounced after self-administered rather than experimenter-administered cocaine, a pattern that was not observed in other regions. We then used rodent tests of attention and decision making to determine whether FosB within the OFC contributes to drug-induced alterations in cognition. Chronic cocaine treatment produced tolerance to the cognitive impairments caused by acute cocaine. Overexpression of a dominant-negative antagonist of FosB, JunD, in the OFC prevented this behavioral adaptation, whereas locally overexpressing FosB mimicked the effects of chronic cocaine. Gene microarray analyses identified potential molecular mechanisms underlying this behavioral change, including an increase in transcription of metabotropic glutamate receptor subunit 5 and GABA_A receptors as well as substance P. Identification of FosB in the OFC as a mediator of tolerance to the effects of cocaine on cognition provides fundamentally new insight into the transcriptional modifications associated with addiction.

Key words: orbitofrontal cortex; addiction; impulsivity; five-choice serial reaction time task; delay-discounting; gene microarray

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Received June 6, 2007; revised Aug. 11, 2007; accepted Aug. 11, 2007.

Correspondence should be addressed to Eric J. Nestler, Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070. Email: eric.nestler{at}utsouthwestern.edu

This article has been cited by other articles:

				C. A. Winstanley, R. K. Bachtell, D. E. H. Theobald, S. Laali, T. A. Green, A. Kumar, S. Chakravarty, D. W. Self, and E. J. Nestler Increased Impulsivity during Withdrawal from Cocaine Self-Administration: Role for {Delta}FosB in the Orbitofrontal Cortex Cereb Cortex, June 6, 2008; (2008) bhn094v1. [Abstract] [Full Text] [PDF]

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