WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine

Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):1395-1400. doi: 10.1073/pnas.1621185114. Epub 2017 Jan 23.


Wiskott-Aldrich syndrome protein (WASP) family verprolin homologous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. Our previous studies have found WAVE1 to be inhibited by Cdk5-mediated phosphorylation in brain and to play a role in the regulation of dendritic spine morphology. Here we report that mice in which WAVE1 was knocked out (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but not mice where WAVE1 was knocked out in neurons expressing the D2 dopamine receptor (D2-KO), exhibited a significant decrease in place preference associated with cocaine. In contrast to wild-type (WT) and WAVE1 D2-KO mice, cocaine-induced sensitized locomotor behavior was not maintained in WAVE1 D1-KO mice. After chronic cocaine administration and following withdrawal, an acute cocaine challenge induced WAVE1 activation in striatum, which was assessed by dephosphorylation. The cocaine-induced WAVE1 dephosphorylation was attenuated by coadministration of either a D1 dopamine receptor or NMDA glutamate receptor antagonist. Upon an acute challenge of cocaine following chronic cocaine exposure and withdrawal, we also observed in WT, but not in WAVE1 D1-KO mice, a decrease in dendritic spine density and a decrease in the frequency of excitatory postsynaptic AMPA receptor currents in medium spiny projection neurons expressing the D1 dopamine receptor (D1-MSNs) in the nucleus accumbens. These results suggest that WAVE1 is involved selectively in D1-MSNs in cocaine-evoked neuronal activity-mediated feedback regulation of glutamatergic synapses.

Keywords: Cdk5; WAVE1; cocaine; medium spiny projection neurons; striatum.

Publication types

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

MeSH terms

  • Animals
  • Cocaine / pharmacology*
  • Dopamine Uptake Inhibitors / pharmacology
  • Electrophysiological Phenomena / genetics
  • Excitatory Postsynaptic Potentials / genetics
  • Excitatory Postsynaptic Potentials / physiology
  • Mice, Knockout
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Neurons / metabolism*
  • Nucleus Accumbens / metabolism
  • Nucleus Accumbens / physiology
  • Phosphorylation / drug effects
  • Receptors, Dopamine D1 / genetics
  • Receptors, Dopamine D1 / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Spatial Behavior / drug effects*
  • Wiskott-Aldrich Syndrome Protein Family / genetics
  • Wiskott-Aldrich Syndrome Protein Family / metabolism*


  • Dopamine Uptake Inhibitors
  • Receptors, Dopamine D1
  • Receptors, N-Methyl-D-Aspartate
  • Wiskott-Aldrich Syndrome Protein Family
  • Cocaine