Project Summary A treatment for drug addiction remains elusive due to incomplete knowledge of the brain circuits controlling both the overwhelming motivation to relapse to drug use and the ability to refrain from using drugs. In part through progress during the 20-yr tenure of this grant, we know that glutamatergic projections from cortical and allocortical brain regions to the nucleus accumbens core (NAcore) and GABAergic NAcore projections to the dorsolateral ventral pallidum (dlVP) are necessary for executing cue-induced cocaine seeking and extinction training-induced refraining from cocaine seeking. Classically, projections from the striatum contain two neuronal subtypes, those projecting to the ventral mesencephalon selectively expressing D1 dopamine receptors (D1-MSNs) and those projecting to the palldum expressing D2 receptors (D2-MSNs). Through work on this grant, we now know that NAcore D1-MSNs also innervate the dlVP1, and that activity in this D1-MSN to dlVP subcircuit is necessary for cue- induced cocaine seeking. Also, we discovered that activity in D2-MSNs is associated with extinction-induced refraining from cocaine seeking. Akin to the NAcore, the dlVP contains two primary cell types, one expressing glutamate (VPglu) and the other expressing GABA (VPGABA). Also, a subpopulation of VPGABA co-express enkephalin (VPPenk). We have begun to study the dlVP subcircuits coded by these distinct dlVP neuronal subtypes in regulating cocaine seeking and refraining from seeking. Cell-type specific chemogenetic stimulation reveals that VPglu inhibit reinstated cocaine seeking and stimulating VPPenk induces cocaine seeking. Surprisingly, VPglu and VPGABA cells in dlVP have different axon terminal fields. These findings indicate distinct roles for the different dlVP neuronal subtypes, and that divergent roles for subtype selective projections emanating from the dlVP is likely. We propose to disentangle the circuitry in which the dlVP is embedded using a combination of behavior, in vivo calcium imaging and slice electrophysiology, and test the hypothesis that VPglu activity promotes refraining during extinction responding, while VPPenk codes for cocaine seeking.