Document Detail

Suppression of endogenous PPARγ increases vulnerability to methamphetamine-induced injury in mouse nigrostriatal dopaminergic pathway.
MedLine Citation:
PMID:  22160138     Owner:  NLM     Status:  MEDLINE    
RATIONALE: 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.
OBJECTIVES: 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.
CONCLUSION: A deficiency in PPARγ increases vulnerability to high doses of methamphetamine. Endogenous PPARγ may play an important role in reducing methamphetamine toxicity in vivo.
Seong-Jin Yu; Mikko Airavaara; Hui Shen; Jenny Chou; Brandon K Harvey; Yun Wang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-12-13
Journal Detail:
Title:  Psychopharmacology     Volume:  221     ISSN:  1432-2072     ISO Abbreviation:  Psychopharmacology (Berl.)     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-14     Completed Date:  2012-11-26     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  7608025     Medline TA:  Psychopharmacology (Berl)     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  479-92     Citation Subset:  IM    
National Institute on Drug Abuse, IRP, Neural Protection and Regeneration Section, 251 Bayview Boulevard, 06-721A, Baltimore, MD 21224, USA.
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MeSH Terms
Behavior, Animal / drug effects
Corpus Striatum / drug effects,  metabolism
Dependovirus / genetics
Dopamine / metabolism*
Dose-Response Relationship, Drug
Integrases / genetics*
Methamphetamine / administration & dosage,  toxicity*
Mice, Inbred C57BL
Mice, Knockout
PPAR gamma / genetics,  metabolism*
Potassium Chloride / pharmacology
Recombination, Genetic
Substantia Nigra / drug effects,  metabolism
Tyrosine 3-Monooxygenase / metabolism
Grant Support
Z01 DA000461-06/DA/NIDA NIH HHS
Reg. No./Substance:
0/PPAR gamma; 537-46-2/Methamphetamine; 7447-40-7/Potassium Chloride; EC 3-Monooxygenase; EC 2.7.7.-/Cre recombinase; EC 2.7.7.-/Integrases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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