title: Differential modulation of methamphetamine-mediated behavioral sensitization by overexpression of Mu opioid receptors in nucleus accumbens and ventral tegmental area.
abstract: BACKGROUND
  Repeated administration of methamphetamine (Meth) induces behavioral sensitization which is characterized by a progressive increase in locomotor response after each injection. Previous studies have shown that Mu opioid receptors (MORs) can regulate Meth-mediated behavioral sensitization. However, the reported interactions are controversial; systemic activation of MORs either enhanced or suppressed Meth sensitization. It is possible that alteration of Meth sensitization after systemic administration of MOR ligands reflects the sum of distinct MOR reactions in multiple brain regions.
  
  
  OBJECTIVE
  The purpose of the present study was to examine the actions of MORs on Meth sensitization after regionally selective overexpression of human MOR through an AAV6-based gene delivery system.
  
  
  METHODS
  We demonstrated that adeno-associated virus (AAV)-MOR increased MOR immunoreactivity and binding in vitro. AAV-MOR or AAV-green fluorescent protein (GFP) was injected into the nucleus accumbens (NAc) or ventral tegmental area (VTA) of adult mice. Two weeks after viral infection, animals received Meth or saline for five consecutive days. Locomotor behavior and striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) level were determined.
  
  
  RESULTS
  Repeated administration of Meth progressively increased locomotor activity; this sensitization reaction was attenuated by intra-NAc AAV-MOR microinjections. Infusion of AAV-MOR to VTA enhanced Meth sensitization. AAV-MOR significantly enhanced DA levels in VTA after VTA infection but reduced DOPAC/DA turnover in the NAc after NAc injection.
  
  
  CONCLUSIONS
  Our data suggest a differential modulation of Meth sensitization by overexpression of MOR in NAc and VTA. Regional manipulation of MOR expression through AAV may be a novel approach to control Meth abuse and psychomimetic activity.
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD, 21224, USA.
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD, 21224, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD, 21224, USA.
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Harvey
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.|Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD, 21224, USA.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Yu
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Theresa
authors.initials: T
authors.lastname: Kopajtic
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD, 21224, USA.
authors.forename: Josh J
authors.initials: JJ
authors.lastname: Hinkle
authors.affiliation: Department of Children's Dentistry, Stony Brook University Health Science Center, Stony Brook, NY, 11794-8701, USA.
authors.forename: Stephanos
authors.initials: S
authors.lastname: Kyrkanides
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD, 21224, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Katz
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan. ywang@intra.nida.nih.gov.|Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD, 21224, USA. ywang@intra.nida.nih.gov.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000096:biosynthesis*; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; D004298:Dopamine
keywords: AAV; Methamphetamine; Mu opioid receptor; Sensitization