Increased Impulsivity during Withdrawal from Cocaine Self-Administration: Role for DFosB 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 DFosB in the OFC that alters the effects of investigatoradministered cocaine on impulsivity. Here, using viral-mediated gene transfer, the effects of overexpressing DFosB within the OFC were assessed on the cognitive sequelae of chronic cocaine selfadministration as measured by the 5-choice serial reaction time task (5CSRT). Cognitive testing occurred in the mornings, and selfadministration 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 DFosB 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 DFosB within the OFC is one mediator of these effects and, thereby, increases vulnerability to addiction.