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 (VPGABA) and glutamatergic (VPGlu) neurons, and a subpopulation of GABAergic neurons co-express enkephalin (VPPenk). Rabies tracing reveals that VPGlu and VPPenk neurons receive preferential innervation from upstream D1- relative to D2-expressing accumbens neurons. Chemogenetic stimulation of VPGlu neurons inhibits, whereas stimulation of VPGABA and VPPenk neurons potentiates cocaine seeking in mice withdrawn from intravenous cocaine self-administration.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, VPGABA neurons increase their overall activity, and VPPenk neurons are selectively activated around nose pokes for cocaine. In contrast, VPGlu neurons increase their spike rate following extinction training. These data show that VP subpopulations differentially encode and regulate cocaine seeking, with VPPenk and VPGABA neurons facilitating and VPGlu neurons inhibiting cocaine seeking. [Display omitted] •Cocaine seeking is potentiated by stimulating GABAergic ventral pallidum neurons•Cocaine seeking is reduced by stimulating glutamatergic ventral pallidal neurons•Glutamate and enkephalin neurons are differentially innervated by accumbens neurons•Calcium is increased during seeking in GABA and during extinction in glutamate neurons Heinsbroek et al. show that glutamate and GABA neurons in ventral pallidum differentially regulate cued cocaine seeking. Calcium activity in glutamate neurons increases when mice refrain from cocaine seeking. Activating glutamate neurons inhibits cocaine seeking. Calcium activity increases in GABA neurons during cocaine seeking, and activating GABA or enkephalin neurons induces cocaine seeking.