Evidence of stimulus attribute‐specificity within the prefrontal cortex (PFC) suggests that different prefrontal subregions may contribute to cocaine addiction in functionally distinct ways. Thus, the present study examined the effects of lidocaine‐induced inactivation of two distinct PFC subregions, the prelimbic (PL) or dorsal agranular insular (AId) cortices, on drug‐seeking and drug‐taking behaviors under cocaine maintenance and reinstatement testing conditions in rats trained to self‐administer 1 mg/kg cocaine under a second‐order schedule of drug delivery. Throughout maintenance and reinstatement phases, rats were exposed to conditioned light cues and contextual odor or sound cues. Results showed that PL inactivation during maintenance test sessions significantly reduced drug‐seeking and drug‐taking behaviors, and disrupted patterns of responding in rats exposed to light–sound, but not light–odor, cues. Moreover, lidocaine‐induced inactivation of the PL significantly attenuated drug‐seeking behavior during cue‐induced and cocaine prime‐induced reinstatement in rats exposed to light–sound cues only. In contrast, AId inactivation significantly attenuated cue‐induced reinstatement of drug‐seeking behavior in rats exposed to light–odor cues only. Drug‐seeking and drug‐taking behaviors in these rats were not disrupted during maintenance and cocaine prime‐induced reinstatement testing regardless of the type of contextual cues used. Together, these data suggest that PL and AId subregions play separate yet overlapping roles in regulating cocaine addiction in rats in ways that are dependent on the presence or absence of cocaine and on the types of contextual cues present in the cocaine self‐administration environment.
