title: Suppression of endogenous PPARγ increases vulnerability to methamphetamine-induced injury in mouse nigrostriatal dopaminergic pathway.
abstract: BACKGROUND
  Methamphetamine is a commonly abused drug and dopaminergic neurotoxin. Repeated administration of high doses of methamphetamine induces programmed cell death, suppression of dopamine release, and reduction in locomotor activity. Previous studies have shown that pretreatment with peroxisome proliferator-activated receptor gamma (PPARγ) agonist reduced methamphetamine-induced neurodegeneration.
  
  
  OBJECTIVE
  The purpose of this study was to examine the role of endogenous PPARγ in protecting against methamphetamine toxicity.
  
  
  METHODS
  Adeno-associated virus (AAV) encoding the Cre recombinase gene was unilaterally injected into the left substantia nigra of loxP-PPARγ or control wild-type mice. Animals were treated with high doses of methamphetamine 1 month after viral injection. Behavioral tests were examined using rotarod and rotometer. In vivo voltammetry was used to examine dopamine release/clearance and at 2 months after methamphetamine injection.
  
  
  RESULTS
  Administration of AAV-Cre selectively removed PPARγ in left nigra in loxP-PPARγ mice but not in the wild-type mice. The loxP-PPARγ/AAV-Cre mice that received methamphetamine showed a significant reduction in time on the rotarod and exhibited increased ipsilateral rotation using a rotometer. The peak of dopamine release induced by local application of KCl and the rate of dopamine clearance were significantly attenuated in the left striatum of loxP-PPARγ/AAV-Cre animals. Tyrosine hydroxylase immunoreactivity was reduced in the left, compared to right, nigra, and dorsal striatum in loxP-PPARγ/AAV-Cre mice receiving high doses of methamphetamine.
  
  
  CONCLUSIONS
  A deficiency in PPARγ increases vulnerability to high doses of methamphetamine. Endogenous PPARγ may play an important role in reducing methamphetamine toxicity in vivo.
authors.affiliation: National Institute on Drug Abuse, IRP, Neural Protection and Regeneration Section, 251 Bayview Boulevard, 06-721A, Baltimore, MD 21224, USA.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Yu
authors.forename: Mikko
authors.initials: M
authors.lastname: Airavaara
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.forename: Jenny
authors.initials: J
authors.lastname: Chou
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Harvey
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019426:Integrases / Q000235:genetics*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D011995:Recombination, Genetic; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D047495:PPAR gamma; D008694:Methamphetamine; D011189:Potassium Chloride; D014446:Tyrosine 3-Monooxygenase; C045073:Cre recombinase; D019426:Integrases; D004298:Dopamine