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

Lauren K K. Dobbs, Alanna R R. Kaplan, Julia C C. Lemos, Aya Matsui, Marcelo Rubinstein, Veronica A A. Alvarez

Research output: Contribution to journalArticlepeer-review

102 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1100-1113
Number of pages14
Issue number5
StatePublished - Jun 1 2016
Externally publishedYes

Bibliographical note

Funding Information:
This study was funded by the Intramural Programs of NIAAA and NINDS (ZIA-AA000421) to V.A.A., and by ANPCYT-Mincyt of Argentina (M.R.), Universidad de Buenos Aires (M.R.) and Tourette Syndrome Association (M.R.). We are grateful to Roland Bock who wrote the Igor procedures used for the voltammetry analysis and to Dr. Ono for access to the confocal microscope and to the members of the V.A.A. lab for helpful comments and discussion. We also thank Dr. B. Roth (UNC) and K. Deisseroth (Stanford) who generously provided the hM4Di and ChR2 constructs, respectively.

Publisher Copyright:
© 2016


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