title: Tolerance and sensitization to chronic escalating dose heroin following extended withdrawal in Fischer rats: possible role of mu-opioid receptors.
abstract: OBJECTIVE
  Heroin addiction is characterized by recurrent cycles of drug use, abstinence, and relapse. It is likely that neurobiological changes during chronic heroin exposure persist across withdrawal and impact behavioral responses to re-exposure. We hypothesized that, after extended withdrawal, heroin-withdrawn rats would express behavioral tolerance and/or sensitization in response to heroin re-exposure and that these responses might be associated with altered mu-opioid receptor (MOPr) activity.
  
  
  METHODS
  Male Fischer rats were exposed chronically to escalating doses of heroin (7.5-75 mg/kg/day), experienced acute spontaneous withdrawal and extended (10-day) abstinence, and were re-exposed chronically to heroin. Homecage behaviors and locomotor activity in response to heroin, as well as somatic withdrawal signs, were recorded. Separate groups of rats were sacrificed after extended abstinence and MOPr expression and G-protein coupling were analyzed using [(3)H]DAMGO and [(35)S]GTPγS assays.
  
  
  RESULTS
  The depth of behavioral stupor was lower during the initial days of heroin re-exposure compared to the initial days of the first exposure period. Behavioral responses (e.g., stereotypy) and locomotion were elevated in response to heroin re-exposure at low doses. Rats conditioned for heroin place preference during the chronic re-exposure period expressed heroin preference during acute withdrawal; this preference was stronger than rats conditioned during chronic heroin exposure that followed chronic saline and injection-free periods. Extended withdrawal was associated with increased MOPr expression in the caudate-putamen and frontal and cingulate cortices. No changes in G-protein coupling were identified.
  
  
  CONCLUSIONS
  Aspects of tolerance/sensitization to heroin are present even after extended abstinence and may be associated with altered MOPr density.
authors: Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. kseip@rockefeller.edu
authors: Katharine M
authors: KM
authors: Seip-Cammack
authors: Brian
authors: B
authors: Reed
authors: Yong
authors: Y
authors: Zhang
authors: Ann
authors: A
authors: Ho
authors: Mary Jeanne
authors: MJ
authors: Kreek
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D003932:Heroin / Q000008:administration & dosage* / Q000009:adverse effects; D006556:Heroin Dependence / Q000503:physiopathology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
chemical_list: D017450:Receptors, Opioid, mu; D003932:Heroin