ΔFosB induction in orbitofrontal cortex mediates tolerance to cocaine-induced cognitive dysfunction

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

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

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 ΔFosB within both medial and orbitofrontal regions of the rat prefrontal cortex. However, the increase in OFC ΔFosB 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 ΔFosB 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 ΔFosB, ΔJunD, in the OFC prevented this behavioral adaptation, whereas locally overexpressing ΔFosB 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 GABAA receptors as well as substance P. Identification of ΔFosB 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.

Original languageEnglish (US)
Pages (from-to)10497-10507
Number of pages11
JournalJournal of Neuroscience
Volume27
Issue number39
DOIs
StatePublished - Sep 26 2007
Externally publishedYes

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Keywords

  • Addiction
  • Delay-discounting
  • Five-choice serial reaction time task
  • Gene microarray
  • Impulsivity
  • Orbitofrontal cortex

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Winstanley, C. A., LaPlant, Q., Theobald, D. E. H., Green, T., Bachtell, R. K., Perrotti, L. I., DiLeone, R. J., Russo, S. J., Garth, W. J., Self, D. W., & Nestler, E. J. (2007). ΔFosB induction in orbitofrontal cortex mediates tolerance to cocaine-induced cognitive dysfunction. Journal of Neuroscience, 27(39), 10497-10507. https://doi.org/10.1523/JNEUROSCI.2566-07.2007