The Circuitry Mediating Cocaine-Induced Reinstatement of Drug-Seeking Behavior

TLDR

The study investigated the contribution of limbic‑striato‑pallidal circuitry to cocaine‑induced reinstatement of drug seeking. Disrupting the VTA‑dPFC‑NAcore‑VP pathway with unilateral GABA agonist injections into dPFC and contralateral VP abolished cocaine reinstatement. Inhibition of motor nuclei, particularly the VP, and dopamine manipulations in the dPFC revealed that dopamine release in the dPFC activates a dPFC‑NAcore‑VP circuit driving cocaine‑induced reinstatement, whereas the VP is not required for food‑related reinstatement.

Abstract

The role of limbic-striato-pallidal circuitry in cocaine-induced reinstatement was evaluated. The transient inhibition of brain nuclei associated with motor systems [including the ventral tegmental area (VTA), dorsal prefrontal cortex (dPFC), core of the nucleus accumbens (NAcore), and ventral pallidum (VP)] prevented cocaine-induced reinstatement. However, only the VP proved to be necessary for food reinstatement, suggesting that the identified circuit is specific to drug-related reinstatement. Supporting the possibility that the VTA-dPFC-NAcore-VP is a series circuit mediating reinstatement, simultaneous unilateral microinjection of GABA agonists into the dPFC in one hemisphere and into the VP in the contralateral hemisphere abolished cocaine reinstatement. Although dopamine projections from the VTA innervate all three forebrain nuclei, the blockade of dopamine receptors only in the dPFC antagonized cocaine-induced reinstatement. Furthermore, DA administration into the dPFC was sufficient to elicit a reinstatement in drug-related responding. These data demonstrate that dopamine release in the dPFC initiates a dPFC-NAcore-VP series circuit that mediates cocaine-induced drug-seeking behavior.