Interactions of the basolateral amygdala with the dorsal hippocampus and dorsomedial prefrontal cortex regulate drug context-induced reinstatement of cocaine-seeking in rats

The basolateral amygdala (BLA), dorsomedial prefrontal cortex (dmPFC) and dorsal hippocampus (DH) are critical elements of the neurocircuitry of drug context-induced reinstatement of cocaine-seeking; however, little is known about functional interactions between these brain regions. The present study tested the hypothesis that serial information processing by the BLA and dmPFC mediates drug context-induced cocaine-seeking, whereas the BLA and DH independently control this behaviour. Rats were trained to self-administer cocaine in a distinct environment (cocaine-paired context) followed by extinction training in a different environment (extinction context). On the test days, rats received unilateral microinfusions of baclofen + muscimol or of vehicle into the BLA and either the contralateral or ipsilateral dmPFC or DH. Cocaine-seeking behaviour (i.e. nonreinforced presses on the cocaine-associated lever) was then assessed in the cocaine-paired and extinction contexts. Following vehicle pretreatment, exposure to the cocaine-paired context reinstated extinguished cocaine-seeking behaviour. BLA-dmPFC asymmetrical inactivation attenuated cocaine-seeking behaviour relative to vehicle treatment; however, this impairment equaled that produced by ipsilateral BLA-dmPFC inactivation. Furthermore, unilateral inactivation of the BLA or dmPFC did not alter this behaviour. BLA-DH asymmetrical inactivation selectively attenuated cocaine-seeking behaviour relative to vehicle treatment whereas ipsilateral or unilateral inactivation of the BLA and DH did not alter this behaviour. These findings indicate that the BLA and DH exhibit sequential information processing within the relapse circuitry. In contrast, interactions between the BLA and dmPFC are more complex and include parallel loops of information processing and/or necessary interhemispheric input from the dmPFC to the BLA, probably in addition to direct intrahemispheric interactions.