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Psychopharmacology

, Volume 221, Issue 3, pp 479–492 | Cite as

Suppression of endogenous PPARγ increases vulnerability to methamphetamine-induced injury in mouse nigrostriatal dopaminergic pathway

  • Seong-Jin Yu
  • Mikko Airavaara
  • Hui Shen
  • Jenny Chou
  • Brandon K. Harvey
  • Yun WangEmail author
Original Investigation

Abstract

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.

Keywords

Methamphetamine Dopamine Neurodegeneration Virus Striatum 

Abbreviations

AAV

Adeno-associated virus

DAPI

4′,6-diamidino-2-phenylindole

DA

Dopamine

ETime

Endurance times

GFP

Green fluorescent protein

GFP/Cre

GFP-Cre fusion protein

KO

Knockout

MA

Methamphetamine

PPARγ

Peroxisome proliferator-activated receptor gamma

PPRE

PPAR response element

RXR

Retinoic X receptor

TH

Tyrosine hydroxylase

WT

Wild type

Notes

Acknowledgment

This study was supported by NIDA IRP. We thank Dr. Barry Hoffer for his critical suggestions.

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Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  • Seong-Jin Yu
    • 1
  • Mikko Airavaara
    • 1
  • Hui Shen
    • 1
  • Jenny Chou
    • 1
  • Brandon K. Harvey
    • 1
  • Yun Wang
    • 1
    Email author
  1. 1.National Institute on Drug Abuse, IRPNeural Protection and Regeneration SectionBaltimoreUSA

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