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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.

Author information

1
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
2
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
3
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
4
Department of Pharmacology and Toxicology, Research Institute on Addictions, Program in Neuroscience, State University of New York at Buffalo, Buffalo, NY 14214.
5
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
6
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065; kimyo@rockefeller.edu greengard@rockefeller.edu.

Abstract

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

PMID:
28115704
PMCID:
PMC5307471
DOI:
10.1073/pnas.1621185114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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