title: Bidirectional Synaptic Structural Plasticity after Chronic Cocaine Administration Occurs through Rap1 Small GTPase Signaling.
abstract: Dendritic spines are the sites of most excitatory synapses in the CNS, and opposing alterations in the synaptic structure of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a primary brain reward region, are seen at early versus late time points after cocaine administration. Here we investigate the time-dependent molecular and biochemical processes that regulate this bidirectional synaptic structural plasticity of NAc MSNs and associated changes in cocaine reward in response to chronic cocaine exposure. Our findings reveal key roles for the bidirectional synaptic expression of the Rap1b small GTPase and an associated local synaptic protein translation network in this process. The transcriptional mechanisms and pathway-specific inputs to NAc that regulate Rap1b expression are also characterized. Collectively, these findings provide a precise mechanism by which nuclear to synaptic interactions induce "metaplasticity" in NAc MSNs, and we reveal the specific effects of this plasticity on reward behavior in a brain circuit-specific manner.
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Michael E
authors: ME
authors: Cahill
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Rosemary C
authors: RC
authors: Bagot
authors: Department of Pharmacology and Toxicology, Research Institute on Addictions, Program in Neuroscience, State University of New York at Buffalo, Buffalo, NY 14214, USA.
authors: Amy M
authors: AM
authors: Gancarz
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Deena M
authors: DM
authors: Walker
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: HaoSheng
authors: H
authors: Sun
authors: Department of Pharmacology and Toxicology, Research Institute on Addictions, Program in Neuroscience, State University of New York at Buffalo, Buffalo, NY 14214, USA.
authors: Zi-Jun
authors: ZJ
authors: Wang
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Elizabeth A
authors: EA
authors: Heller
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Jian
authors: J
authors: Feng
authors: Department of Psychology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Pamela J
authors: PJ
authors: Kennedy
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Ja Wook
authors: JW
authors: Koo
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Hannah M
authors: HM
authors: Cates
authors: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors: Rachael L
authors: RL
authors: Neve
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Li
authors: L
authors: Shen
authors: Department of Pharmacology and Toxicology, Research Institute on Addictions, Program in Neuroscience, State University of New York at Buffalo, Buffalo, NY 14214, USA.
authors: David M
authors: DM
authors: Dietz
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: eric.nestler@mssm.edu.
authors: Eric J
authors: EJ
authors: Nestler
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012201:Reward; D064067:Rho Guanine Nucleotide Exchange Factors; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D020668:rap GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C574809:ARHGEF11 protein, mouse; D000199:Actins; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C492135:Rap1b protein, rat; D020668:rap GTP-Binding Proteins; D003042:Cocaine