Increased impulsivity during withdrawal from cocaine self-administration: role for DeltaFosB in the orbitofrontal cortex.
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 DeltaFosB in the OFC that alters the effects of investigator-administered cocaine on impulsivity. Here, using viral-mediated gene transfer, the effects of overexpressing DeltaFosB 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 DeltaFosB 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 DeltaFosB within the OFC is one mediator of these effects and, thereby, increases vulnerability to addiction.
Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
Catharine A
CA
Winstanley
Ryan K
RK
Bachtell
David E H
DE
Theobald
Samuel
S
Laali
Thomas A
TA
Green
Arvind
A
Kumar
Sumana
S
Chakravarty
David W
DW
Self
Eric J
EJ
Nestler
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003042:Cocaine / Q000009:adverse effects*; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000523:psychology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000502:physiology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007150:Immunohistochemistry; D007175:Impulsive Behavior / Q000235:genetics* / Q000523:psychology*; D008297:Male; D017397:Prefrontal Cortex / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D011930:Reaction Time / Q000502:physiology; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000235:genetics* / Q000523:psychology*
D016760:Proto-Oncogene Proteins c-fos; D003042:Cocaine