title: Chaperone heat shock protein 70 in nucleus accumbens core: a novel biological target of behavioural sensitization to morphine in rats.
abstract: Drug addiction is a major public health issue, yet the underlying adaptation of neural networks by drugs of abuse is not fully understood. We have previously linked chaperone heat shock protein 70 (Hsp70) to drug-induced adaptations. Focusing on the NAc core and shell, the present study aims to provide further findings for our understanding of the relation between behavioural sensitization to morphine and Hsp70 at transcriptional and functional levels in rats. Firstly, we delineated the characteristics of behavioural sensitization induced by a single morphine exposure (1-10 mg/kg, s.c.). Secondly, Hsp70 protein expression in the NAc core was time- and dose-relatedly induced during the development of behavioural sensitization to a single morphine exposure in rats, and Pearson analysis indicated a positive correlation between behavioural sensitization and Hsp70 expression in NAc core. Thirdly, at the transcriptional level, intra-NAc core injection of the specific heat shock factor-I (HSF-I) inhibitor N-Formyl-3,4-methylenedioxy-benzylidine-γ-butyrolactam (KNK437) suppressed Hsp70 expression and the development of behavioural sensitization, while the HSF-I specific inducer geranylgeranylacetone (GGA) promoted both of them. Interestingly, intra-NAc shell injection of KNK437 or GGA did not affect the development of behavioural sensitization. Finally, both the functional inhibition of Hsp70 ATPase activity by methylene blue (MB), and the antagonism of Hsp70 substrate binding site (SBD) activity by pifithrin-μ (PES) impaired the development of behavioural sensitization when they were microinjected into the NAc core. Taken together, the critical involvement of chaperone Hsp70 in behavioural sensitization to morphine identifies a biological target for long-lasting adaptations with relevance to addiction.
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, China-Japan Friendship Hospital, Beijing 100029, China.
authors.forename: Wang-Jun
authors.initials: WJ
authors.lastname: Qin
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Li
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liang
authors.affiliation: Florey Institute of Neuroscience & Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: Florey Institute of Neuroscience & Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lawrence
authors.affiliation: Department of Pharmacy, China-Japan Friendship Hospital, Beijing 100029, China.
authors.forename: Xiang-Lin
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Jian-Hui
authors.initials: JH
authors.lastname: Liang
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D008297:Male; D008751:Methylene Blue / Q000008:administration & dosage; D008845:Microinjections; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
chemical_list: C545747:2-phenylacetylenesulfonamide; D000701:Analgesics, Opioid; D001559:Benzhydryl Compounds; D004224:Diterpenes; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; C410027:KNK 437; D011760:Pyrrolidinones; D013449:Sulfonamides; D009020:Morphine; C031049:geranylgeranylacetone; D008751:Methylene Blue