title: WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine.
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.
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Ceglia
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
authors.forename: Ko-Woon
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cahill
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Graves
authors.affiliation: Department of Pharmacology and Toxicology, Research Institute on Addictions, Program in Neuroscience, State University of New York at Buffalo, Buffalo, NY 14214.
authors.forename: David
authors.initials: D
authors.lastname: Dietz
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Dalton J
authors.initials: DJ
authors.lastname: Surmeier
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.|Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065; kimyo@rockefeller.edu greengard@rockefeller.edu.
authors.forename: Paul
authors.identifier: 0000-0002-4437-0893
authors.initials: P
authors.lastname: Greengard
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065; kimyo@rockefeller.edu greengard@rockefeller.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Kim
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D055724:Electrophysiological Phenomena / Q000235:genetics; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013037:Spatial Behavior / Q000187:drug effects*; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics / Q000378:metabolism*
chemical_list: D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D051300:Wiskott-Aldrich Syndrome Protein Family; D003042:Cocaine
keywords: Cdk5; WAVE1; cocaine; medium spiny projection neurons; striatum