title: Interactions between N-ethylmaleimide-sensitive factor and GluR2 in the nucleus accumbens contribute to the expression of locomotor sensitization to cocaine.
abstract: Many studies have reported a withdrawal-dependent increase in synaptic AMPA receptor (AMPAR) levels in the nucleus accumbens (NAc) of cocaine-sensitized rats; however, the exact relationship between the expression of sensitization and altered AMPAR surface expression in the NAc has not yet been investigated. We demonstrated that the expression of behavioral sensitization was negatively controlled by N-ethylmaleimide-sensitive factor (NSF)-GluR2 interactions in the NAc. The upregulation of NSF-GluR2 interactions, which may be resulted by the increase in NSF S-nitrosylation after withdrawal from cocaine, was associated with the changes in the expression of behavioral sensitization. Disruption of NSF-GluR2 interactions in the NAc with a specific peptide, TAT-pep-R845A, increased the locomotor response of rats to cocaine by decreasing GluR2 surface insertion. In contrast, prevention of GluR2-containing AMPARs removal from synapses with Pep2-EVKI attenuated the expression of behavioral sensitization. Similarly, treatment with the nitric oxide donor, S-Nitroso-N-acetyl-DL-penicillamine (SNAP), attenuated the expression of locomotor sensitization by promoting GluR2 surface expression. This effect was mediated by the binding of S-nitrosylated NSF to GluR2, which promoted the surface expression of AMPARs. Noticeably, exogenous injection of SNAP into NAc also attenuated the expression of cocaine-induced conditioned place preference. Thus, these results indicate that increased NSF-GluR2 interactions in the NAc after withdrawal from cocaine attenuated the expression of behavioral sensitization and serves as a negative regulatory mechanism in drug-exposed individuals.
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China, Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Hubei 430030, China, and The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei 430030, China.
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Lu
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wu
authors.forename: Yuan-Jian
authors.initials: YJ
authors.lastname: Yang
authors.forename: Wen
authors.initials: W
authors.lastname: Xiao
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Yuan-Long
authors.initials: YL
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Zhuang-Li
authors.initials: ZL
authors.lastname: Hu
authors.forename: You
authors.initials: Y
authors.lastname: Jin
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D008297:Male; D008845:Microinjections / Q000379:methods; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000096:biosynthesis* / Q000235:genetics; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000096:biosynthesis* / Q000235:genetics; D013375:Substance Withdrawal Syndrome / Q000378:metabolism
chemical_list: D018091:Receptors, AMPA; D052066:N-Ethylmaleimide-Sensitive Proteins; C498737:Nsf protein, rat; D003042:Cocaine; C104722:glutamate receptor ionotropic, AMPA 2