Opposing Regulation of Cocaine Seeking by Glutamate and GABA Neurons in the Ventral Pallidum

Projections from the nucleus accumbens to the ventral pallidum (VP) regulate relapse in animal models of addiction. The VP contains GABAergic (VP(GABA)) and glutamatergic (VP(Glu)) neurons, and a subpopulation of GABAergic neurons co-express enkephalin (VP(Penk)). Rabies tracing reveals that VP(Glu) and VP(Penk) neurons receive preferential innervation from upstream D1- relative to D2-expressing accumbens neurons. Chemogenetic stimulation of VP(Glu) neurons inhibits, whereas stimulation of VP(GABA) and VP(Penk) neurons potentiates cocaine seeking in mice withdrawn from intravenous cocaine self-administration. Calcium imaging reveals cell type-specific activity patterns when animals learn to suppress drug seeking during extinction training versus engaging in cue-induced cocaine seeking. During cued seeking, VP(GABA) neurons increase their overall activity, and VP(Penk) neurons are selectively activated around nose pokes for cocaine. In contrast, VP(Glu) neurons increase their spike rate following extinction training. These data show that VP subpopulations differentially encode and regulate cocaine seeking, with VP(Penk) and VP(GABA) neurons facilitating and VP(Glu) neurons inhibiting cocaine seeking.