Dopamine Regulation of Lateral Inhibition between Striatal Neurons Gates the Stimulant Actions of Cocaine

Neuron. 2016 Jun 1;90(5):1100-13. doi: 10.1016/j.neuron.2016.04.031. Epub 2016 May 12.


Striatal medium spiny neurons (MSNs) form inhibitory synapses on neighboring striatal neurons through axon collaterals. The functional relevance of this lateral inhibition and its regulation by dopamine remains elusive. We show that synchronized stimulation of collateral transmission from multiple indirect-pathway MSNs (iMSNs) potently inhibits action potentials in direct-pathway MSNs (dMSNs) in the nucleus accumbens. Dopamine D2 receptors (D2Rs) suppress lateral inhibition from iMSNs to disinhibit dMSNs, which are known to facilitate locomotion. Surprisingly, D2R inhibition of synaptic transmission was larger at axon collaterals from iMSNs than their projections to the ventral pallidum. Targeted deletion of D2Rs from iMSNs impaired cocaine's ability to suppress lateral inhibition and increase locomotion. These impairments were rescued by chemogenetic activation of Gi-signaling in iMSNs. These findings shed light on the functional significance of lateral inhibition between MSNs and offer a novel synaptic mechanism by which dopamine gates locomotion and cocaine exerts its canonical stimulant response. VIDEO ABSTRACT.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Central Nervous System Sensitization / drug effects
  • Central Nervous System Sensitization / physiology
  • Cocaine / pharmacology*
  • Corpus Striatum / cytology*
  • Corpus Striatum / drug effects*
  • Corpus Striatum / physiology
  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • Locomotion / drug effects*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neural Inhibition / drug effects*
  • Neural Inhibition / physiology*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / physiology
  • Receptors, Dopamine D2 / physiology


  • Receptors, Dopamine D2
  • Cocaine
  • Dopamine