Dopaminergic Control of Striatal Cholinergic Interneurons Underlies Cocaine-Induced Psychostimulation

Robert G. Lewis; Marcello Serra; Daniela Radl; Michela Gori; Catherine Tran; Sharon E. Michalak; Christopher D. Vanderwal; Emiliana Borrelli

Cell Reports (Apr 2020)

Dopaminergic Control of Striatal Cholinergic Interneurons Underlies Cocaine-Induced Psychostimulation

Robert G. Lewis,
Marcello Serra,
Daniela Radl,
Michela Gori,
Catherine Tran,
Sharon E. Michalak,
Christopher D. Vanderwal,
Emiliana Borrelli

Affiliations

Robert G. Lewis: Department of Microbiology & Molecular Genetics, U1233 INSERM, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA 92697, USA
Marcello Serra: Department of Microbiology & Molecular Genetics, U1233 INSERM, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA 92697, USA
Daniela Radl: Department of Microbiology & Molecular Genetics, U1233 INSERM, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA 92697, USA
Michela Gori: Department of Microbiology & Molecular Genetics, U1233 INSERM, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA 92697, USA
Catherine Tran: Department of Microbiology & Molecular Genetics, U1233 INSERM, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA 92697, USA
Sharon E. Michalak: Department of Chemistry, University of California, Irvine, Irvine, CA 92697, USA
Christopher D. Vanderwal: Department of Chemistry, University of California, Irvine, Irvine, CA 92697, USA
Emiliana Borrelli: Department of Microbiology & Molecular Genetics, U1233 INSERM, Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA 92697, USA; Corresponding author

Journal volume & issue: Vol. 31, no. 3

Abstract

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Summary: Cocaine drastically elevates dopamine (DA) levels in the striatum, a brain region that is critical to the psychomotor and rewarding properties of the drug. DA signaling regulates intrastriatal circuits connecting medium spiny neurons (MSNs) with afferent fibers and interneurons. While the cocaine-mediated increase in DA signaling on MSNs is well documented, that on cholinergic interneurons (ChIs) has been more difficult to assess. Using combined pharmacological, chemogenetic, and cell-specific ablation approaches, we reveal that the D2R-dependent inhibition of acetylcholine (ACh) signaling is fundamental to cocaine-induced changes in behavior and the striatal genomic response. We show that the D2R-dependent control of striatal ChIs enables the motor, sensitized, and reinforcing properties of cocaine. This study highlights the importance of the DA- and D2R-mediated inhibitory control of ChIs activity in the normal functioning of striatal networks. : Cocaine increases striatal dopamine, which is responsible for the psychomotor effects of the drug. Lewis et al. analyze how alterations of D2R signaling in cholinergic interneurons affect cocaine-mediated responses and show that the absence of D2R reduces the motor response to the drug and abolishes its reinforcing properties. Keywords: striatum, cocaine, acetylcholine, dopamine, cholingeric interneuron, medium spiny neurons, dopamine D2 receptor, ChI-D2RKO mice, addiction, reward

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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