Dopaminergic Control of Striatal Cholinergic Interneurons Underlies Cocaine-Induced Psychostimulation

Cell Rep. 2020 Apr 21;31(3):107527. doi: 10.1016/j.celrep.2020.107527.


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.

Keywords: ChI-D2RKO mice; acetylcholine; addiction; cholingeric interneuron; cocaine; dopamine; dopamine D2 receptor; medium spiny neurons; reward; striatum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Animals
  • Cholinergic Neurons / drug effects*
  • Cholinergic Neurons / metabolism
  • Cocaine / pharmacology*
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism
  • Dopamine / metabolism*
  • Female
  • Interneurons / drug effects*
  • Interneurons / metabolism
  • Mice
  • Mice, Knockout
  • Muscarinic Antagonists / pharmacology
  • Receptors, Dopamine D2 / deficiency
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Muscarinic / metabolism
  • Signal Transduction / drug effects
  • Transcriptome / drug effects


  • DRD2 protein, mouse
  • Muscarinic Antagonists
  • Receptors, Dopamine D2
  • Receptors, Muscarinic
  • Cocaine
  • Acetylcholine
  • Dopamine