title: Circadian alteration in neurobiology during 30 days of abstinence in heroin users.
abstract: BACKGROUND
  Previous studies have shown that individuals withdrawn from chronic opiate administration undergo substantial elevations of cortisol levels with blunted corticotropin (ACTH) rhythms and that these changes persist beyond the 7-10 days of acute withdrawal symptoms. However, there are no published studies of changes in expression of clock genes or of other neuropeptides related to circadian-rhythm regulation, which may influence relapse susceptibility.
  
  
  METHODS
  Blood samples were collected from 8 healthy control subjects and 16 heroin addicts during pharmacologically unassisted withdrawal on the 3rd, 10th, and 30th days of abstinence at 3-hour intervals for 24 hours. Outcome measures were the relative expression of clock gene mRNA (hperiod1, hperiod2, hclock) and the levels of serum cortisol, plasma ACTH, beta-endorphin (beta-EP), leptin, neuropeptide Y, interleukin-2 (IL-2), and tumor necrosis factor (TNF) in these subjects.
  
  
  RESULTS
  Compared with healthy volunteers, abstinent addicts showed disruptions in diurnal rhythms of hPER1 and hPER2 mRNA expression, along with disruptions in diurnal rhythms of cortisol, ACTH, beta-endorphin, leptin, and IL-2 release. Several of these disruptions (hPER1, hPER2, ACTH, beta-endorphin, and IL-2) persisted for the 30-day testing period, as did elevation of 24-hour levels of cortisol and decreases in 24-hour IL-2 and TNF levels.
  
  
  CONCLUSIONS
  These prolonged neurobiological changes may play a role in protracted opiate withdrawal symptoms and contribute to relapse vulnerability.
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing 100083, China.
authors.forename: Su-xia
authors.initials: SX
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.forename: David H
authors.initials: DH
authors.lastname: Epstein
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Xiao-li
authors.initials: XL
authors.lastname: Zhang
authors.forename: Yan-ping
authors.initials: YP
authors.lastname: Bao
authors.forename: Dai
authors.initials: D
authors.lastname: Zhang
authors.forename: Xiang-yang
authors.initials: XY
authors.lastname: Zhang
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kosten
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000818:Animals; D056926:CLOCK Proteins; D016022:Case-Control Studies; D021081:Chronobiology Disorders / Q000378:metabolism*; D055030:Drug Users; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D006556:Heroin Dependence / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007031:Hypothalamus / Q000378:metabolism*; D007376:Interleukin-2 / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008297:Male; D009478:Neuropeptide Y / Q000097:blood; D009687:Nuclear Proteins / Q000097:blood / Q000378:metabolism; D056950:Period Circadian Proteins; D012313:RNA / Q000378:metabolism; D051381:Rats; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000097:blood / Q000378:metabolism; D014157:Transcription Factors / Q000097:blood / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D001615:beta-Endorphin / Q000097:blood
chemical_list: D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D009478:Neuropeptide Y; D009687:Nuclear Proteins; C539022:PER1 protein, human; C421902:PER2 protein, human; C539024:Per1 protein, rat; D056950:Period Circadian Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D001615:beta-Endorphin; D012313:RNA; D000324:Adrenocorticotropic Hormone; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D056926:CLOCK Proteins; C538943:CLOCK protein, human; C538945:Clock protein, rat; D006854:Hydrocortisone