Essential Role for Rac1 in Cocaine-Induced Structural Plasticity of Nucleus Accumbens Neurons

Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here we show that repeated exposure to cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. Further, we show, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1 or local knockout of Rac1 is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 or light activation of a photoactivatable form of Rac1 blocks the ability of repeated cocaine exposure to produce this effect. Downregulation of Rac1 activity likewise promotes behavioral responses to cocaine exposure, with activation of Rac1 producing the opposite effect. These findings establish that Rac1 signaling mediates structural and behavioral plasticity in response to cocaine exposure.

• Publication year

  2012

• Venue

  Nature Neuroscience

• Publication date

  2012-03-26

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/nn.3094PMID 22522400PMCID 3565539
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Calcium-Permeable AMPA Receptors Are Present in Nucleus Accumbens Synapses after Prolonged Withdrawal from Cocaine Self-Administration But Not Experimenter-Administered Cocaine

  2011cited by this paper
• Association of anxiety and depression with microtubule-associated protein 2- and synaptopodin-immunolabeled dendrite and spine densities in hippocampal CA3 of older humans.

  2010cited by this paper
• MeCP2 in the Nucleus Accumbens Contributes to Neural and Behavioral Responses to Psychostimulants

  2010cited by this paper
• Tiam1 as a Signaling Mediator of Nerve Growth Factor-Dependent Neurite Outgrowth

  2010cited by this paper
• Essential Role of the Histone Methyltransferase G9a in Cocaine-Induced Plasticity

  2010cited by this paper
• Regulation of Synaptic Rac1 Activity, Long-Term Potentiation Maintenance, and Learning and Memory by BCR and ABR Rac GTPase-Activating Proteins

  2010cited by this paper
• Behavioral and morphological responses to cocaine require kalirin7.

  2010cited by this paper
• Disrupted-in-Schizophrenia-1 (DISC1) regulates spines of the glutamate synapse via Rac1

  2010cited by this paper
• Cocaine‐induced neuroadaptations in glutamate transmission

  2010cited by this paper
• Inhibition of Actin Polymerization Prevents Cocaine-induced Changes in Spine Morphology in the Nucleus Accumbens

  2010cited by this paper
• The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens.

  2010cited by this paper
• Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens

  2010cited by this paper
• The Bermuda Triangle of cocaine-induced neuroadaptations.

  2010cited by this paper
• Experience-dependent structural synaptic plasticity in the mammalian brain

  2009cited by this paper
• The glutamate homeostasis hypothesis of addiction

  2009cited by this paper
• In vivo cocaine experience generates silent synapses.

  2009cited by this paper
• A genetically-encoded photoactivatable Rac controls the motility of living cells

  2009cited by this paper
• Rac1 deficiency in the forebrain results in neural progenitor reduction and microcephaly.

  2009cited by this paper
• Altered Dendritic Spine Plasticity in Cocaine-Withdrawn Rats

  2009cited by this paper
• Rac1 GTPase: A “Rac” of All Trades

  2009cited by this paper
• Nuclear Factor κB Signaling Regulates Neuronal Morphology and Cocaine Reward

  2009cited by this paper
• Neuroplasticity in the mesolimbic dopamine system and cocaine addiction

  2008cited by this paper
• Cocaine regulates MEF2 to control synaptic and behavioral plasticity.

  2008cited by this paper
• Dendritic spine dynamics--a key role for kalirin-7.

  2008cited by this paper
• Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA.

  2008cited by this paper
• TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology

  2006cited by this paper
• Cocaine Increases Actin Cycling: Effects in the Reinstatement Model of Drug Seeking

  2006cited by this paper
• Neural mechanisms of addiction: the role of reward-related learning and memory.

  2006cited by this paper
• MinireviewUnmanageable Motivation in Addiction : A Pathology in Prefrontal-Accumbens Glutamate Transmission

  2005cited by this paper
• Structural plasticity associated with exposure to drugs of abuse.

  2004cited by this paper
• Cofilin Promotes Actin Polymerization and Defines the Direction of Cell Motility

  2004cited by this paper
• The small GTP-binding protein RhoA regulates c-jun by a ROCK-JNK signaling axis.

  2004cited by this paper
• Regulation of dendritic spine motility and stability by Rac1 and Rho kinase: evidence for two forms of spine motility.

  2004cited by this paper
• Hematopoietic Cell Regulation by Rac1 and Rac2 Guanosine Triphosphatases

  2003cited by this paper
• Prefrontal Glutamate Release into the Core of the Nucleus Accumbens Mediates Cocaine-Induced Reinstatement of Drug-Seeking Behavior

  2003cited by this paper
• Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5.

  2003cited by this paper
• CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli

  2002cited by this paper
• Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex

  2002cited by this paper
• Structure and function of dendritic spines.

  2002cited by this paper
• Dentritic spines : structure, dynamics and regulation

  2001cited by this paper
• Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine

  2001cited by this paper
• Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and Rho.

  2000cited by this paper
• Actin and the agile spine: how and why do dendritic spines dance?

  2000cited by this paper
• Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and Rho.

  2000cited by this paper
• Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics

  1999cited by this paper
• Rho GTPases Control Polarity, Protrusion, and Adhesion during Cell Movement

  1999cited by this paper
• Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia

  1998cited by this paper
• Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization

  1998cited by this paper
• Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines

  1996cited by this paper
• Supporting Online Material Materials and Methods Som Text Figs. S1 to S8 References Cell Type–specific Loss of Bdnf Signaling Mimics Optogenetic Control of Cocaine Reward

  year unknowncited by this paper
• OCAINE REGULATES EZRIN – RADIXIN – MOESIN PROTEINS AND hoA SIGNALING IN THE NUCLEUS ACCUMBENS

  year unknowncited by this paper

• Identification of an engram ensemble mediating memory forgetting in the dentate gyrus.

  2026cites this paper
• Reducing astrocyte calcium in the nucleus accumbens core increases reward valuation

  2025cites this paper
• Prefrontal circHomer1 regulates synaptic and behavioral adaptations induced by cocaine

  2025cites this paper
• Intersectin1/cdc42 signaling regulates methamphetamine-induced neuronal remodeling in the hippocampus

  2025cites this paper
• Split-Small GTPase Reassembly as a Method to Control Cellular Signaling with User-Defined Inputs

  2025cites this paper
• Split-Small GTPase Reassembly as a Method to Control Cellular Signaling with User-Defined Inputs

  2025cites this paper
• Synaptic Plasticity Linked to Ionotropic Glutamate Receptors After Nicotine Exposure

  2025cites this paper
• The impact of temporal distribution on fear extinction learning

  2025cites this paper
• Phospho-CREB Regulation on NMDA Glutamate Receptor 2B and Mitochondrial Calcium Uniporter in the Ventrolateral Periaqueductal Gray Controls Chronic Morphine Withdrawal in Male Rats

  2025cites this paper
• GluN2B-mediated regulation of silent synapses for receptor specification and addiction memory

  2025influential citation
• LASP1 in the nucleus accumbens modulates methamphetamine-induced conditioned place preference in mice.

  2024cites this paper
• ERK2 Signaling in the Nucleus Accumbens Facilitates Stress Susceptibility and Cocaine Reinstatement

  2024cites this paper
• Disrupting heroin-associated memory reconsolidation through actin polymerization inhibition in the nucleus accumbens core

  2024cites this paper
• Targeting Tiam1 Enhances Hippocampal-Dependent Learning and Memory in the Adult Brain and Promotes NMDA Receptor-Mediated Synaptic Plasticity and Function

  2024cites this paper
• The Small G-Protein Rac1 in the Dorsomedial Striatum Promotes Alcohol-Dependent Structural Plasticity and Goal-Directed Learning in Mice

  2024cites this paper
• Standardized Parts for Activation of Small GTPase Signaling in Living Cells

  2024cites this paper
• Targeting the cytoskeleton as a therapeutic approach to substance use disorders

  2024cites this paper
• Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

  2024cites this paper
• The mutated cytoplasmic fragile X messenger ribonucleoprotein 1 (FMR1)‐interacting protein 2 (CYFIP2 S968F) regulates cocaine‐induced reward behaviour and plasticity in the nucleus accumbens

  2024cites this paper
• Cofilin linked to GluN2B subunits of NMDA receptors is required for behavioral sensitization by changing the dendritic spines of neurons in the caudate and putamen after repeated nicotine exposure

  2024influential citation
• Roles of Rac1-Dependent Intrinsic Forgetting in Memory-Related Brain Disorders: Demon or Angel

  2023cites this paper
• Investigating role of ASIC2 in synaptic and behavioral responses to drugs of abuse

  2023cites this paper
• Methamphetamine-induced region-specific transcriptomic and epigenetic changes in the brain of male rats

  2023cites this paper
• Viral-mediated expression of Erk2 in the nucleus accumbens regulates responses to rewarding and aversive stimuli

  2023cites this paper
• Rac 1 controls synaptic strength through the regulation of synaptic vesicle 1 priming 2 3 ( Abbreviated title ) : Presynaptic Rac 1 regulates synaptic strength 4

  2022cites this paper
• Cognitive Dysfunction and Prefrontal Cortical Circuit Alterations in Schizophrenia: Developmental Trajectories.

  2022cites this paper
• Up‐regulation of cell division cycle 20 expression alters the morphology of neuronal dendritic spines in the nucleus accumbens by promoting FMRP ubiquitination

  2022cites this paper
• Cdc42 signaling regulated by dopamine D2 receptor correlatively links specific brain regions of hippocampus to cocaine addiction.

  2022cites this paper
• Presynaptic Rac1 controls synaptic strength through the regulation of synaptic vesicle priming

  2022cites this paper
• The Use of Drosophila to Understand Psychostimulant Responses

  2022cites this paper
• Time of Day-Dependent Alteration of Hippocampal Rac1 Activation Regulates Contextual Fear Memory in Rats

  2022cites this paper
• ABCC1 regulates cocaine-associated memory, spine plasticity and GluA1 and GluA2 surface expression

  2021cites this paper
• Mice carrying a schizophrenia-associated mutation of the Arhgap10 gene are vulnerable to the effects of methamphetamine treatment on cognitive function: association with morphological abnormalities in striatal neurons

  2021cites this paper
• Chronic opipramol treatment extinguishes cocaine craving through Rac1 in responders: A rat model study

  2021cites this paper
• In vivo reduction of hippocampal Caveolin-1 by RNA interference alters morphine addiction and neuroplasticity changes in male mice.

  2021cites this paper
• Spinophilin modulates pain through suppressing dendritic spine morphogenesis via negative control of Rac1-ERK signaling in rat spinal dorsal horn.

  2021cites this paper
• Interactions of neuroimmune signaling and glutamate plasticity in addiction

  2021cites this paper
• Stress-induced vulnerability to develop cocaine addiction depends on cofilin modulation

  2021cites this paper
• Astrocytes in Cocaine Addiction and Beyond

  2021cites this paper
• Cell-Type-Specific Adaptions in Striatal Medium-Sized Spiny Neurons and Their Roles in Behavioral Responses to Drugs of Abuse

  2021cites this paper
• Development of a versatile HPLC-based method to evaluate the activation status of small GTPases

  2021cites this paper
• Bidirectional role of dopamine in learning and memory-active forgetting.

  2021cites this paper
• AP-1 controls the p11-dependent antidepressant response

  2020cites this paper
• Flying Together: Drosophila as a Tool to Understand the Genetics of Human Alcoholism

  2020cites this paper
• Stress-Sensitive Protein Rac1 and Its Involvement in Neurodevelopmental Disorders

  2020cites this paper
• Dietary phytochemicals modulate experience-dependent changes in Neurexin gene expression and alternative splicing in mice after chronic variable stress exposure.

  2020cites this paper
• The Rac-GEF Tiam1 Promotes Dendrite and Synapse Stabilization of Dentate Granule Cells and Restricts Hippocampal-Dependent Memory Functions

  2020cites this paper
• Engineering Optogenetic Protein Analogs.

  2020cites this paper
• The Role of Rac GTPase in Dendritic Spine Morphogenesis and Memory

  2020cites this paper
• Integrated analysis profiles of long non–coding RNAs reveal potential biomarkers across brain regions in post–traumatic stress disorder

  2020cites this paper
• The potential involvement of miR-204-3p-axon guidance network in methamphetamine-induced locomotor sensitization of mice.

  2019cites this paper
• Silent Synapses Dictate Cocaine Memory Destabilization and Reconsolidation

  2019cites this paper
• Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens

  2019cites this paper
• Sema3E/PlexinD1 signaling inhibits postischemic angiogenesis by regulating endothelial DLL4 and filopodia formation in a rat model of ischemic stroke

  2019cites this paper
• Controlling protein conformation with light.

  2019cites this paper
• Encoding the β-Arrestin Trafficking Fate of Ghrelin Receptor GHSR1a: C-Tail-Independent Molecular Determinants in GPCRs.

  2019cites this paper
• Dopamine D1 and D2 Receptors Differentially Regulate Rac1 and Cdc42 Signaling in the Nucleus Accumbens to Modulate Behavioral and Structural Plasticity After Repeated Methamphetamine Treatment.

  2019cites this paper
• Regulation of signaling proteins in the brain by light.

  2019cites this paper
• Dynamic CRMP2 Regulation of CaV2.2 in the Prefrontal Cortex Contributes to the Reinstatement of Cocaine Seeking

  2019cites this paper
• Neural Morphology and Addiction

  2019cites this paper
• Synaptic Microtubule-Associated Protein EB3 and SRC Phosphorylation Mediate Structural and Behavioral Adaptations During Withdrawal From Cocaine Self-Administration

  2019cites this paper
• Blue Light-Induced Gene Expression Alterations in Cultured Neurons Are the Result of Phototoxic Interactions with Neuronal Culture Media

  2019cites this paper
• Post-translational S-glutathionylation of cofilin increases actin cycling during cocaine seeking

  2019cites this paper
• The Rac3 GTPase in Neuronal Development, Neurodevelopmental Disorders, and Cancer

  2019cites this paper
• Genetic dissection of active forgetting in labile and consolidated memories in Drosophila

  2019cites this paper
• Altered Actin Filament Dynamics in the Drosophila Mushroom Bodies Lead to Fast Acquisition of Alcohol Consumption Preference

  2019cites this paper
• Optical control of neuronal ion channels and receptors

  2019cites this paper
• P-Rex1 Overexpression Results in Aberrant Neuronal Polarity and Psychosis-Related Behaviors

  2019cites this paper
• Role of Mesolimbic Ghrelin in the Acquisition of Cocaine Reward.

  2019cites this paper
• Cocaine addicted to cytoskeletal change and a fibrosis high

  2019cites this paper
• The trafficking protein JFC1 regulates Rac1‐GTP localization at the uropod controlling neutrophil chemotaxis and in vivo migration

  2019cites this paper
• Glutamate delta-1 receptor regulates cocaine-induced plasticity in the nucleus accumbens

  2018cites this paper
• Granulocyte-colony stimulating factor controls neural and behavioral plasticity in response to cocaine

  2018cites this paper
• Ghrelin receptor antagonism of hyperlocomotion in cocaine‐sensitized mice requires βarrestin‐2

  2018cites this paper
• Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice

  2018cites this paper
• The dendritic spine morphogenic effects of repeated cocaine use occur through the regulation of serum response factor signaling

  2018cites this paper
• Neural, Cellular and Molecular Mechanisms of Active Forgetting

  2018cites this paper
• Potential of microRNAs as novel targets in the alleviation of pathological fear

  2018cites this paper
• Withdrawal from repeated morphine administration augments expression of the RhoA network in the nucleus accumbens to control synaptic structure

  2018cites this paper
• E3 Ubiquitin-Protein Ligase SMURF1 in the Nucleus Accumbens Mediates Cocaine Seeking.

  2018cites this paper
• Neuronal mechanisms mediating pathological reward‐related behaviors: A focus on silent synapses in the nucleus accumbens

  2018cites this paper
• Granulocyte-Colony-Stimulating Factor Alters the Proteomic Landscape of the Ventral Tegmental Area

  2018cites this paper
• mTORC2 in the dorsomedial striatum of mice contributes to alcohol-dependent F-Actin polymerization, structural modifications, and consumption

  2018cites this paper
• Morphological Plasticity in the Striatum Associated With Dopamine Dysfunction

  2017cites this paper
• Role of Nicotinamide N-Methyltransferase in Dorsal Striatum in Cocaine Place Preference

  2017influential citation
• It's only a matter of time: longevity of cocaine-induced changes in dendritic spine density in the nucleus accumbens.

  2017cites this paper
• The Arf6 Activator Efa6/PSD3 Confers Regional Specificity and Modulates Ethanol Consumption in Drosophila and Humans

  2017cites this paper
• Affecting long-term fear memory formation through optical control of Rac1 GTPase and PAK activity in lateral amygdala

  2017cites this paper
• Cross-talk between the epigenome and neural circuits in drug addiction.

  2017cites this paper
• Optogenetic approaches for dissecting neuromodulation and GPCR signaling in neural circuits.

  2017cites this paper
• Fear Conditioning Downregulates Rac1 Activity in the Basolateral Amygdala Astrocytes to Facilitate the Formation of Fear Memory

  2017cites this paper
• Optogenetic Tools for Subcellular Applications in Neuroscience.

  2017cites this paper
• Reward Circuitry in Addiction

  2017cites this paper
• Drp1 Mitochondrial Fission in D1 Neurons Mediates Behavioral and Cellular Plasticity during Early Cocaine Abstinence.

  2017cites this paper
• Roundabout receptor 2 maintains inhibitory control of the adult midbrain

  2017cites this paper
• Cdk5 Is Essential for Amphetamine to Increase Dendritic Spine Density in Hippocampal Pyramidal Neurons

  2017cites this paper
• Very Long-Term Effects of Chronic Cocaine on Anxiety and Stress

  2017cites this paper
• Layer 3 Excitatory and Inhibitory Circuitry in the Prefrontal Cortex: Developmental Trajectories and Alterations in Schizophrenia.

  2017cites this paper
• Label-Free Neuroproteomics of the Hippocampal-Accumbal Circuit Reveals Deficits in Neurotransmitter and Neuropeptide Signaling in Mice Lacking Ethanol-Sensitive Adenosine Transporter.

  2017cites this paper
• Rapid Synaptogenesis in the Nucleus Accumbens Is Induced by a Single Cocaine Administration and Stabilized by Mitogen-Activated Protein Kinase Interacting Kinase-1 Activity.

  2017cites this paper