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

Jasper A Heinsbroek,Ana-Clara Bobadilla,Eric Dereschewitz,Ahlem Assali,Reda M Chalhoub,Christopher W Cowan,Peter W Kalivas

doi:10.1016/j.celrep.2020.01.023

Jasper A Heinsbroek, Ana-Clara Bobadilla + Show 5 more

Open Access

https://doi.org/10.1016/j.celrep.2020.01.023

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Abstract

SUMMARYProjections 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of VPGlu neurons inhibits, whereas stimulation of VPGABA and VPPenk neurons potentiates cocaine seeking in mice withdrawn from intravenous cocaine self-administration.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.

Highlights

The interconnected nuclei of the ventral basal ganglia regulate motivated behavior and reward learning
ventral pallidum (VP) Neuronal Subtypes: Anatomical Distinctions We used in situ hybridization (RNAscope) to quantify neuron subtype density in subcommissural dorsal VP—VPGlu (23%), VP contains GABAergic (VPGABA) (73%), and VPPenk (16%)—and found that >90% of VPPenk and
The dorsal VP (dVP) is innervated by the core subcompartment of the accumbens (NAcore) (Heimer et al, 1991), and we used a retrograde rabies labeling strategy to determine the relative innervation of the distinct dVP cell types by NAcore D1- and D2-MSNs

Summary

Introduction

The interconnected nuclei of the ventral basal ganglia regulate motivated behavior and reward learning. Activation of VPGlu neurons drives aversion (Faget et al, 2018; Tooley et al, 2018), whereas stimulating VPGABA neurons motivates reward seeking (Faget et al, 2018; Zhu et al, 2017) These effects are mediated in part by projections to the ventral tegmental area (VTA) and lateral habenula (lHb) (Faget et al, 2018)

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