Journal
JOURNAL OF NEUROSCIENCE
Volume 27, Issue 39, Pages 10497-10507Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2566-07.2007
Keywords
orbitofrontal cortex; addiction; impulsivity; five-choice serial reaction time task; delay-discounting; gene microarray
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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 Delta FosB within both medial and orbitofrontal regions of the rat prefrontal cortex. However, the increase in OFC Delta 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 Delta 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 Delta FosB, Delta JunD, in the OFC prevented this behavioral adaptation, whereas locally overexpressing Delta 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 Delta 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.
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