Orbitofrontal cortex (OFC) damage produces impaired decision-making, impulsivity, and perseveration of maladaptive behaviors and it potentially contributes to compulsive drug seeking in cocaine users. To investigate whether lOFC damage contributes to enhanced context-induced cocaine seeking in an animal model of drug relapse, the effects of lOFC temporary functional inactivation, pre-training lesions, and post-training lesions were assessed on the reinstatement of previously extinguished cocaine-seeking behavior (i.e., non-reinforced responses on a previously cocaine-paired lever). All rats were trained to lever press for intravenous cocaine infusions (0.2 mg/infusion) in a distinct environmental context followed by extinction training in a different context where cocaine was not available. In experiment 1 we assessed whether acute loss of lOFC output alters context-induced cocaine-seeking behavior by infusing either the GABA receptor agonists, baclofen and muscimol (1.0 mM, 0.5 µl/side), or vehicle into the lOFC or mOFC anatomical control region immediately before re-exposure to the cocaine-paired context. To evaluate the effects of long-term loss of lOFC output on this behavior, in experiment 2 we assessed the effects of pre-training bilateral NMDA (0.1 M, 0.6 µl/side) or sham lesions of the lOFC on cocaine-seeking behavior elicited by either re-exposure to the cocaine-paired context or a cocaine priming injection (0 or 10 mg/kg, i.p.) administered immediately before exposure to the extinction context. GABA agonist-induced functional inactivation of the lOFC, but not mOFC, significantly attenuated context-induced cocaine seeking (Fuchs et al., 2004). In contrast, pre-training lOFC lesions enhanced cocaine context-induced cocaine seeking, but failed to alter cocaine-primed cocaine seeking. To identify whether the timing of the lOFC manipulation underlies this discrepancy, in experiment 3 we assessed the effects of post-training lOFC lesions on context-induced cocaine-seeking behaviors. In contrast to the effects of pre-training lesions and functional inactivation, post-training lOFC lesions failed to alter context-induced cocaine-seeking behavior. Overall, the results of the functional inactivation experiment suggest that the lOFC promotes context-induced cocaine-seeking behavior. However, prolonged loss of lOFC output may enhance the motivational salience of the cocaine-paired environmental stimuli by eliciting compensatory neuroadaptations, which may develop over time such that the effects of post-training lOFC lesions reflect an intermediate state of compensatory neuroplasticity
