The present study tested the hypothesis that separate neural substrates mediate cocaine relapse elicited by drug-associated contextual stimuli vs explicit conditioned stimuli (CSs) and cocaine. Specifically, we investigated the involvement of the dorsal hippocampus (DH), basolateral amygdala (BLA), and dorsomedial prefrontal cortex (dmPFC) in contextual reinstatement of cocaine-seeking behavior and the involvement of the DH in explicit CS- and cocaine-induced reinstatement. Rats were trained to self-administer cocaine in a distinct context or in the presence of CSs paired explicitly with cocaine infusions. Responding of context-trained rats was then extinguished in the previously cocaine-paired or an alternate context, whereas responding of explicit CS- trained rats was extinguished in the absence of the CSs. Subsequently, the target brain regions or anatomical control regions were functionally inactivated using tetrodotoxin ( 0 or 5 ng/ side), and cocaine-seeking behavior (ie, nonreinforced responses) was assessed in the cocaine-paired context, in the alternate context, in the presence of the explicit CSs, or following cocaine priming ( 10 mg/kg, i.p.). DH inactivation abolished contextual, but failed to alter explicit CS- or cocaine-induced, reinstatement of cocaine-seeking behavior. BLA or dmPFC inactivation also abolished contextual reinstatement. Conversely, inactivation of the control brain regions failed to alter contextual reinstatement. In conclusion, the DH, BLA, and dmPFC play critical roles in contextual reinstatement. Previous findings suggest that the BLA is critical for explicit CS- induced, but not cocaine-primed, reinstatement and the dmPFC is critical for both explicit CS- induced and cocaine-primed reinstatement. Thus, distinct but partially overlapping neural substrates mediate context-induced, explicit CS- induced, and cocaine-primed reinstatement of extinguished cocaine-seeking behavior.
