DeltaFosB induction in orbitofrontal cortex mediates tolerance to cocaine-induced cognitive dysfunction.
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 deltaFosB within both medial and orbitofrontal regions of the rat prefrontal cortex. However, the increase in OFC deltaFosB 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 deltaFosB 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 deltaFosB, deltaJunD, in the OFC prevented this behavioral adaptation, whereas locally overexpressing deltaFosB 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 deltaFosB 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.
Winstanley
Catharine A
CA
Department of Psychiatry and Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
LaPlant
Quincey
Q
Theobald
David E H
DE
Green
Thomas A
TA
Bachtell
Ryan K
RK
Perrotti
Linda I
LI
DiLeone
Ralph J
RJ
Russo
Scott J
SJ
Garth
William J
WJ
Self
David W
DW
Nestler
Eric J
EJ
D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000209:etiology / Q000503:physiopathology; D003072:Cognition Disorders / Q000139:chemically induced / Q000503:physiopathology*; D004195:Disease Models, Animal; D004361:Drug Tolerance / Q000502:physiology*; D005625:Frontal Lobe / Q000187:drug effects*; D020869:Gene Expression Profiling; D018014:Gene Transfer Techniques; D008297:Male; D009483:Neuropsychological Tests; D020411:Oligonucleotide Array Sequence Analysis; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley
D000697:Central Nervous System Stimulants; C483820:Fosb protein, rat; D016760:Proto-Oncogene Proteins c-fos; D003042:Cocaine