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

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

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Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Department of Pharmacology and Toxicology, Research Institute on Addictions, Program in Neuroscience, State University of New York at Buffalo, Buffalo, NY 14214.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;


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.


Cdk5; WAVE1; cocaine; medium spiny projection neurons; striatum

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Conflict of interest statement

The authors declare no conflict of interest.

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