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

Projections from the nucleus accumbens to the ventral pallidum (VP) regulate drug relapse. The VP contains predominately GABAergic (VPGABA) and glutamatergic (VP Glu) neurons, and a subpopulation of GABAergic neurons co-express enkephalin (VPPenk). Rabies tracing revealed that VPGlu and VPPenk receive a high proportion of innervation from D1- relative to D2-expressing accumbens neurons, while GABAergic cells receive equivalent D1- and D2-innervation. Chemogenetic stimulation of each VP subtype showed that VPGlu inhibit, while VPPenk potentiate cocaine-seeking in mice withdrawn from cocaine self-administration. Miniature microscopic calcium imaging for each neuronal cell-type revealed distinct activity patterns during extinction training and relapse to cocaine-seeking. VPPenk were selectivity activated around nosepokes during cue-induced cocaine-seeking, whereas VPGlu neurons increased their spike rate following extinction training, and their activity negatively regulated drug seeking during reinstatement. These data show that VP subpopulations differentially encode and regulate cocaine seeking, with VPPenk facilitating and VPGlu inhibiting cocaine seeking in extinguished mice.