Designer Receptors Show Role for Ventral Pallidum Input to Ventral Tegmental Area in Cocaine Seeking

Ventral pallidum (VP) is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to ventral tegmental area (VTA) regulates neuronal activity there. However, VP is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear. Here we demonstrate that projections to VTA from rostral (RVP), but not caudal VP (CVP) are robustly Fos-activated during cue-induced reinstatement of cocaine seeking—a rat model of relapse in addiction. Moreover, designer receptor-mediated transient inactivation of RVP neurons, their terminals in VTA, or functional connectivity between RVP and VTA dopamine neurons blocks the ability of drug-associated cues (but not a cocaine prime) to reinstate cocaine seeking. In contrast, CVP neuronal inhibition instead blocked cocaine-primed, but not cue-induced reinstatement. This novel double dissociation in VP sub-regional roles in drug seeking is likely important for understanding mesocorticolimbic circuits underlying reward seeking and addiction.