Involvement of a mesocorticolimbic subcircuit in the reinstatement of drug context-induced cocaine seeking behavior in rats

The orbitofrontal cortex (OFC) and basolateral amygdala (BLA) control the ability of cocaine-paired environmental contexts to elicit relapse in addicts and cocaine-seeking behavior in laboratory animals. Whether these brain regions interact within a single neural circuitry or work independently to control this behavior remains to be ascertained. Given that extensive anatomical connections exist between the OFC and BLA, it was postulated that serial information processing occurs between these brain regions. To test this hypothesis, Experiment 1 utilized a functional disconnection procedure to disrupt communication between the OFC and BLA. Rats received microinfusions of the GABAA/B agonists, baclofen+muscimol (BM) or vehicle (VEH) unilaterally into the OFC plus the contralateral or ipsilateral BLA immediately before tests for cocaine-seeking behavior (responding on a previously cocaine-paired lever) in the cocaine-paired context or an alternate context (extinction context). Exposure to the previously cocaine-paired context, but not the extinction context, reinstated extinguished cocaine-seeking behavior. BM treatment in the OFC plus the contralateral or ipsilateral BLA attenuated this behavior relative to VEH, suggesting that inter- and intra-hemispheric interactions between the OFC and BLA are critical for drug context-induced motivation for cocaine. Next, Experiment 2 evaluated whether dopamine D1 receptor stimulation in the OFC contributed to drug context-induced cocaine seeking. The dopamine D1-like receptor antagonist, SCH23390, or VEH was administered bilaterally into the OFC before testing. Intra-OFC SCH23390 treatment dose-dependently attenuated drug context-induced cocaine seeking relative to VEH, implicating dopamine D1 receptors in drug context-induced motivation for cocaine. The ventral tegmental area (VTA) provides the sole source of dopamine to the OFC. Therefore, Experiment 3 assessed whether dopamine input from the VTA to the OFC critically regulates interactions between the OFC and BLA. SCH23390 or VEH was administered unilaterally into the OFC plus BM or VEH into the contralateral or ipsilateral BLA before testing. The SCH23390/BM manipulation attenuated drug context-induced cocaine seeking relative to VEH. Together, these findings indicate that the VTA regulates both interhemispheric and intrahemispheric interactions between the OFC and BLA via the stimulation of dopamine D1 receptors in the OFC and that this newly characterized VTA-BLA-OFC neural circuit promotes drug context-induced motivation for cocaine