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Involvement of the lateral orbitofrontal cortex in drug context‐induced reinstatement of cocaine‐seeking behavior in rats

Orbitofrontal cortex (OFC) damage produces impaired decision‐making, impulsivity and perseveration and potentially contributes to compulsive drug seeking in cocaine users. To further explore this phenomenon, we assessed the role of the lateral OFC (lOFC) in drug context‐induced cocaine‐seeking behavior in the reinstatement model of drug relapse. Rats were trained to lever press for intravenous cocaine infusions in a distinct environmental context (cocaine‐paired context) followed by extinction training in a different context (extinction‐paired context). Reinstatement of cocaine seeking (non‐reinforced lever presses) was assessed in the cocaine context in the absence of response‐contingent stimuli. In Experiment 1, we evaluated whether acute inhibition of lOFC output alters context‐induced cocaine‐seeking behavior by infusing the GABAB + A agonists (baclofen + muscimol) or vehicle into the lOFC immediately before exposure to the cocaine‐paired context. In Experiments 2 and 3, we assessed how prolonged loss of lOFC output affects drug context‐induced cocaine seeking by administering bilateral N‐methyl‐d‐aspartic acid or sham lesions of the lOFC either before or after self‐administration and extinction training. Remarkably, IOFC functional inactivation attenuated, post‐training lesions failed to alter and pre‐training lesions potentiated drug context‐induced cocaine seeking without altering responding in the extinction context. These results suggest that neural activity in the lOFC promotes context‐induced cocaine‐seeking behavior. However, prolonged loss of lOFC output enhances the motivational salience of cocaine‐paired contextual stimuli probably by eliciting compensatory neuroadaptations, with the effects of post‐training lOFC lesions reflecting an intermediate state of compensatory neuroplasticity. Overall, these findings support the idea that OFC dysfunction may promote cue reactivity and enhance relapse propensity in cocaine users.