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Cerebral Cortex Advance Access originally published online on June 6, 2008
Cerebral Cortex 2009 19(2):435-444; doi:10.1093/cercor/bhn094
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© The Author 2008. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Increased Impulsivity during Withdrawal from Cocaine Self-Administration: Role for {Delta}FosB in the Orbitofrontal Cortex

Catharine A. Winstanley1, Ryan K. Bachtell, David E.H. Theobald, Samuel Laali, Thomas A. Green, Arvind Kumar, Sumana Chakravarty, David W. Self and Eric J. Nestler

Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA

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

Increased impulsivity caused by addictive drugs is believed to contribute to the maintenance of addiction and has been linked to hypofunction within the orbitofrontal cortex (OFC). Recent data indicate that cocaine "self-administration" induces the transcription factor {Delta}FosB in the OFC that alters the effects of investigator-administered cocaine on impulsivity. Here, using viral-mediated gene transfer, the effects of overexpressing {Delta}FosB within the OFC were assessed on the cognitive sequelae of chronic cocaine self-administration as measured by the 5-choice serial reaction time task (5CSRT). Cognitive testing occurred in the mornings, and self-administration sessions in the evenings, to enable the progressive assessment of repeated volitional drug intake on performance. Animals self-administering cocaine initially made more omissions and premature or impulsive responses on the 5CSRT but quickly developed tolerance to these disruptive effects. However, withdrawal from cocaine dramatically increased premature responding. When access to cocaine was increased, animals overexpressing {Delta}FosB failed to regulate their intake as effectively and were more impulsive during withdrawal. In summary, rats develop tolerance to the cognitive disruption caused by cocaine self-administration and show a deficit in impulse control that is unmasked during withdrawal. Our findings suggest that induction of {Delta}FosB within the OFC is one mediator of these effects and, thereby, increases vulnerability to addiction.

Key Words: addiction • 5-choice serial reaction time task • relapse • transcription factors • withdrawal

1 Current address: Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver BC, V6T 1Z4, Canada


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