Abstract
Background
Substance use disorder is a neurobiological disease characterized by episodes of relapse
despite periods of withdrawal. It is thought that neuroadaptations in discrete brain
areas of the reward pathway, including the nucleus accumbens, underlie these aberrant
behaviors. The ubiquitin–proteasome system degrades proteins and has been shown to
be involved in cocaine-induced plasticity, but the role of E3 ubiquitin ligases, which
conjugate ubiquitin to substrates, is unknown. Here, we examined E3 ubiquitin-protein
ligase SMURF1 (SMURF1) in neuroadaptations and relapse behavior during withdrawal
following cocaine self-administration.
Methods
SMURF1 and downstream targets ras homolog gene family, member A (RhoA), SMAD1/5, and
Runt-related transcript factor 2 were examined using Western blotting (n = 9–11/group), quantitative polymerase chain reaction (n = 6–9/group), co-immunoprecipitation (n = 9–11/group), tandem ubiquitin binding entities affinity purification (n = 5–6/group), and quantitative chromatin immunoprecipitation (n = 3–6/group) (2 rats/sample). Viral-mediated gene transfer (n = 7–12/group) and intra-accumbal microinjections (n = 9–10/group) were used to examine causal roles of SMURF1 and substrate RhoA, respectively,
in cue-induced cocaine seeking.
Results
SMURF1 protein expression was decreased, while SMURF1 substrates RhoA and SMAD1/5
were increased, in the nucleus accumbens on withdrawal day 7, but not on withdrawal
day 1, following cocaine self-administration. Viral-mediated gene transfer of Smurf1 or constitutive activation of RhoA attenuated cue-induced cocaine seeking, while
catalytically inactive Smurf1 enhanced cocaine seeking. Furthermore, SMURF1-regulated, SMAD1/5-associated transcription
factor Runt-related transcript factor 2 displayed increased binding at promoter regions
of genes previously associated with cocaine-induced plasticity.
Conclusions
SMURF1 is a key mediator of neuroadaptations in the nucleus accumbens following cocaine
exposure and mediates cue-induced cocaine seeking during withdrawal.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Diagnostic and Statistical Manual of Mental Disorders, 5th ed..American Psychiatric Association, Washington, DC2013
- Evolving conceptualizations of cocaine dependence.in: Kosten T.R. Herbert H.D. Clinician’s Guide to Cocaine Addiction: Theory, Research and Treatment. Guilford, New York1992: 33-52
- Brain circuitry and the reinstatement of cocaine-seeking behavior.Psychopharmacology (Berl). 2003; 168: 44-56
- The reinstatement model of drug relapse: Recent neurobiological findings, emerging research topics, and translational research.Psychopharmacology (Berl). 2013; 229: 453-476
- The proteasome and epigenetics: Zooming in on histone modifications.Biomol Concepts. 2016; 7: 215-227
- The ubiquitin-proteasome pathway and synaptic plasticity.Learn Mem. 2010; 17: 314-327
- The ubiquitin-proteasome system as a critical regulator of synaptic plasticity and long-term memory formation.Neurobiol Learn Mem. 2013; 105: 107-116
- Roles of the ubiquitin proteasome system in the effects of drugs of abuse.Front Mol Neurosci. 2015; 7: 99
- Proteolysis, synaptic plasticity and memory.Neurobiol Learn Mem. 2017; 138: 98-110
- Ubiquitin in postsynaptic function and plasticity.Annu Rev Cell Dev Biol. 2010; 26: 179-210
- Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction.Nat Rev Neurosci. 2008; 9: 826-838
- Tau phosphorylation, molecular chaperones, and ubiquitin E3 ligase: Clinical relevance in Alzheimer’s disease.J Alzheimers Dis. 2015; 43: 341-361
- Parkin plays a role in sporadic Parkinson’s disease.Neurodegener Dis. 2014; 13: 69-71
- Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B.Gene. 2015; 573: 33-45
- A critical role for protein degradation in the nucleus accumbens core in cocaine reward memory.Neuropsychopharmacology. 2013; 38: 778-790
- Response of the ubiquitin proteasome system to memory retrieval after extended-access cocaine or saline self-administration.Neuropsychopharmacology. 2015; 40: 3006-3014
- Regulation of cell polarity and protrusion formation by targeting RhoA for degradation.Science. 2003; 302: 1775-1779
- A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation.Nature. 1999; 400: 687-693
- Localized recruitment and activation of RhoA underlies dendritic spine morphology in a glutamate receptor-dependent manner.J Cell Biol. 2006; 172: 453-467
- AMPA receptor and GEF-H1/Lfc complex regulates dendritic spine development through RhoA signaling cascade.Proc Natl Acad Sci U S A. 2009; 106: 3549-3554
- Inhibition of Rho via Arg and p190RhoGAP in the postnatal mouse hippocampus regulates dendritic spine maturation, synapse and dendrite stability, and behavior.J Neurosci. 2007; 27: 10982-10992
- Prenatal cocaine exposure increases synaptic localization of a neuronal RasGEF, GRASP-1 via hyperphosphorylation of AMPAR anchoring protein, GRIP.PLoS One. 2011; 6: e25019
- Integrin β1 signals through Arg to regulate postnatal dendritic arborization, synapse density, and behavior.J Neurosci. 2012; 32: 2824-2834
- Environmental enrichment alters protein expression as well as the proteomic response to cocaine in rat nucleus accumbens.Front Behav Neurosci. 2014; 8: 246
- Role of nicotinamide N-methyltransferase in dorsal striatum in cocaine place preference.Neuropsychopharmacology. 2017; 42: 2333-2343
- Cocaine regulates ezrin-radixin-moesin proteins and RhoA signaling in the nucleus accumbens.Neuroscience. 2009; 163: 501-505
- BMP-Smad 1/5/8 signalling in the development of the nervous system.Prog Neurobiol. 2013; 109: 28-41
- Toxin-induced activation of the G protein p21 Rho by deamidation of glutamine.Nature. 1997; 387: 729-733
- Gln 63 of Rho is deamidated by Escherichia coli cytotoxic necrotizing factor-1.Nature. 1997; 387: 725-729
- Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior [published online ahead of print Aug 17].Mol Psychiatry. 2018;
- Between-session progressive ratio performance in rats responding for cocaine and water reinforcers.Psychopharmacology (Berl). 2012; 222: 215-223
- Activin receptor signaling regulates cocaine-primed behavioral and morphological plasticity.Nat Neurosci. 2015; 18: 959-961
- BRG1 in the nucleus accumbens regulates cocaine-seeking behavior.Biol Psychiatry. 2016; 80: 652-660
- Use of herpes virus amplicon vectors to study brain disorders.BioTechniques. 2005; 39: 381-391
- The Rat Brain in Stereotaxic Coordinates.Elselvier, Burlington, MA2009
- Effects of the trace amine-associated receptor 1 agonist RO5263397 on abuse-related effects of cocaine in rats.Neuropsychopharmacology. 2014; 39: 2309-2316
- Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving.Nat Neurosci. 2014; 17: 73-80
- Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving.Nature. 2008; 453: 118-121
- Alterations in AMPA receptor subunits and TARPs in the rat nucleus accumbens related to the formation of Ca2+-permeable AMPA receptors during the incubation of cocaine craving.Neuropharmacology. 2011; 61: 1141-1151
- Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic gamma-actin levels.J Cell Biol. 2015; 211: 569-586
- Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons.Nat Neurosci. 2012; 15: 891-896
- Dishevelled-2 regulates cocaine-induced structural plasticity and Rac1 activity in the nucleus accumbens.Neurosci Lett. 2015; 598: 23-28
- Transforming growth factor beta receptor 1 is increased following abstinence from cocaine self-administration, but not cocaine sensitization.PLoS One. 2013; 8: e83834
- Efficient protection and isolation of ubiquitylated proteins using tandem ubiquitin-binding entities.EMBO Rep. 2009; 10: 1250-1258
- The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis.Nat Neurosci. 2004; 7: 364-372
- Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons.J Neurosci. 2000; 20: 5329-5338
- Regulation of dendritic spine morphology by the rho family of small GTPases: Antagonistic roles of Rac and Rho.Cereb Cortex. 2000; 10: 927-938
- RhoA/ROCK regulation of neuritogenesis via profilin IIa-mediated control of actin stability.J Cell Biol. 2003; 162: 1267-1279
- Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine.Proc Natl Acad Sci U S A. 2009; 106: 16859-16864
- A model of NMDA receptor control of F-actin treadmilling in synaptic spines and their growth.Bull Math Biol. 2011; 73: 2109-2131
- Stress and trauma: BDNF control of dendritic-spine formation and regression.Prog Neurobiol. 2014; 112: 80-99
- A RUNX2/PEBP2alpha A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia.Proc Natl Acad Sci U S A. 2000; 97: 10549-10554
- Smad function and intranuclear targeting share a Runx2 motif required for osteogenic lineage induction and BMP2 responsive transcription.J Cell Physiol. 2005; 204: 63-72
- Integration of Runx and Smad regulatory signals at transcriptionally active subnuclear sites.Proc Natl Acad Sci U S A. 2002; 99: 8048-8053
- Transcriptional and epigenetic mechanisms of addiction.Nat Rev Neurosci. 2011; 12: 623-637
- The bone-specific transcriptional regulator Cbfa1 is a target of mechanical signals in osteoblastic cells.J Biol Chem. 2002; 277: 23934-23941
- Physical interaction of the activator protein-1 factors c-Fos and c-Jun with Cbfa1 for collagenase-3 promoter activation.J Biol Chem. 2002; 277: 816-822
- Cellular responses to chronic treatment with drugs of abuse.Crit Rev Neurobiol. 1993; 7: 23-39
- Beyond neuronal activity markers: Select immediate early genes in striatal neuron subtypes functionally mediate psychostimulant addiction.Front Behav Neurosci. 2017; 11: 112
- Neural mechanisms of addiction: The role of reward-related learning and memory.Annu Rev Neurosci. 2006; 29: 565-598
- Is there a common molecular pathway for addiction?.Nat Neurosci. 2005; 8: 1445-1449
- Drp1 mitochondrial fission in D1 neurons mediates behavioral and cellular plasticity during early cocaine abstinence.Neuron. 2017; 96: 1327-1341
- Opposing role for Egr3 in nucleus accumbens cell subtypes in cocaine action.J Neurosci. 2015; 35: 7927-7937
- Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system.Nat Neurosci. 2003; 6: 231-242
- Nucleus accumbens neurons exhibit synaptic scaling that is occluded by repeated dopamine pre-exposure.Eur J Neurosci. 2009; 30: 539-550
- Proteasome phosphorylation regulates cocaine-induced sensitization.Mol Cell Neurosci. 2017; 88: 62-69
- PSMC5, a 19S proteasomal ATPase, regulates cocaine action in the nucleus accumbens.PLoS One. 2015; 10: e0126710
- Neural substrates of cue reactivity: Association with treatment outcomes and relapse.Addict Biol. 2016; 21: 3-22
- Synaptic mechanisms underlying persistent cocaine craving.Nat Rev Neurosci. 2016; 17: 351-365
- The addicted synapse: Mechanisms of synaptic and structural plasticity in nucleus accumbens.Trends Neurosci. 2010; 33: 267-276
- Epigenetic mechanisms of drug addiction.Neuropharmacology. 2014; 76: 259-268
- Rho GTPases and signaling networks.Genes Dev. 1997; 11: 2295-2322
- Rho GTPases and the actin cytoskeleton.Science. 1998; 279: 509-514
- Binding of RhoA by the C2 domain of E3 ligase Smurf1 is essential for Smurf1-regulated RhoA ubiquitination and cell protrusive activity.FEBS Lett. 2011; 585: 2199-2204
- Pivotal role of the C2 domain of the Smurf1 ubiquitin ligase in substrate selection.J Biol Chem. 2011; 286: 16861-16870
- It’s only a matter of time: Longevity of cocaine-induced changes in dendritic spine density in the nucleus accumbens.Curr Opin Behav Sci. 2017; 13: 117-123
- Cocaine increases actin cycling: effects in the reinstatement model of drug seeking.J Neurosci. 2006; 26: 1579-1587
- Rho GTPases regulate distinct aspects of dendritic arbor growth in Xenopus central neurons in vivo.Nat Neurosci. 2000; 3: 217-225
- Regulation of rho GTPases by crosstalk and neuronal activity in vivo.Neuron. 2002; 33: 741-750
- The neuronal architecture of Xenopus retinal ganglion cells is sculpted by rho-family GTPases in vivo.J Neurosci. 1999; 19: 8454-8463
- Essential roles of Drosophila RhoA in the regulation of neuroblast proliferation and dendritic but not axonal morphogenesis.Neuron. 2000; 25: 307-316
- Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex.Synapse. 2001; 39: 257-266
- Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine.Eur J Neurosci. 1999; 11: 1598-1604
- Amphetamine or cocaine limits the ability of later experience to promote structural plasticity in the neocortex and nucleus accumbens.Proc Natl Acad Sci U S A. 2003; 100: 10523-10528
- A Smad action turnover switch operated by WW domain readers of a phosphoserine code.Genes Dev. 2011; 25: 1275-1288
- Retrograde BMP signaling at the synapse: A permissive signal for synapse maturation and activity-dependent plasticity.J Neurosci. 2013; 33: 17937-17950
Article info
Publication history
Published online: July 20, 2018
Accepted:
July 10,
2018
Received in revised form:
June 25,
2018
Received:
April 2,
2018
Identification
Copyright
© 2018 Society of Biological Psychiatry.
