title: AMPA receptor upregulation in the nucleus accumbens shell of cocaine-sensitized rats depends upon S-nitrosylation of stargazin.
abstract: Behavioral sensitization to cocaine is associated with increased AMPA receptor (AMPAR) surface expression in the nucleus accumbens (NAc). This upregulation is withdrawal-dependent, as it is not detected on withdrawal day (WD) 1, but is observed on WD7-21. Its underlying mechanisms have not been clearly established. Nitric oxide (NO) regulates AMPAR trafficking in the brain by S-nitrosylation of the AMPAR auxiliary subunit, stargazin, leading to increased AMPAR surface expression. Our goal was to determine if stargazin S-nitrosylation contributes to AMPAR upregulation during sensitization. First, we measured stargazin S-nitrosylation in NAc core and shell subregions on WD14 after 8 daily injections of saline or 15 mg/kg cocaine. Stargazin S-nitrosylation was markedly increased in NAc shell but not core. To determine if this is associated with AMPAR upregulation, rats received 8 cocaine or saline injections followed by twice-daily treatments with vehicle or the nitric oxide synthase inhibitor l-NAME (50 mg/kg) on WD1-6, the time when AMPAR upregulation is developing in cocaine-exposed rats. Cocaine/vehicle rats showed elevated stargazin and GluA1 surface expression on WD7 compared to saline/vehicle rats; the GluA1 increase was more robust in core, while stargazin increased more robustly in shell. These effects of cocaine were attenuated in shell but not core when cocaine injections were followed by l-NAME treatment on WD1-6. Together, these results indicate that elevated S-nitrosylation of stargazin contributes to AMPAR upregulation during sensitization selectively in the NAc shell. It is possible that AMPAR upregulation in core involves a different TARP, γ4, which also upregulates in the NAc of sensitized rats.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience and Departments of Pharmacology and Molecular Sciences and Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Balakrishnan
authors.initials: B
authors.lastname: Selvakumar
authors.affiliation: Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Campbell
authors.affiliation: Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL.
authors.forename: Mike
authors.initials: M
authors.lastname: Milovanovic
authors.affiliation: Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL.
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Park
authors.affiliation: Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: West
authors.affiliation: The Solomon H. Snyder Department of Neuroscience and Departments of Pharmacology and Molecular Sciences and Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
authors.affiliation: Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL.
authors.forename: Marina E
authors.initials: ME
authors.lastname: Wolf
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
chemical_list: C491911:Cacng2 protein, rat; D015220:Calcium Channels; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D003042:Cocaine
keywords: AMPA receptor; AMPAR; BS(3); Ca(2+)/calmodulin-dependent protein kinase II; CaMKII; Cocaine; NAc; NO; NOS; Nitric oxide synthase; Nitrosylation; Nucleus accumbens; SNP; Stargazin; TARP; WD; bis(sulfosuccinimidyl)suberate; l-NAME; l-NG-Nitroarginine Methyl Ester; nNOS; neuronal NOS; nitric oxide; nitric oxide synthase; nucleus accumbens; sodium nitroprusside; transmembrane AMPA receptor regulatory protein; withdrawal day
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