Suppression of endogenous proliferator-activated receptor gamma increases vulnerability to methamphetamine –induced injury in mouse nigrostriatal dopaminergic pathway

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NIDA	NEURO/BEHAV/SENSYS-32

* FARE Award Winner

Authors

• SJ Yu
• H Shen
• BK Harvey
• Y Wang

Abstract

Repeated administration of high doses of methamphetamine induces dopaminergic degeneration and reduction in locomotor activity. The purpose of this study was to examine the role of endogenous peroxisome proliferator-activated receptor gamma (PPARr) in protecting against methamphetamine toxicity. Adeno-associated virus (AAV) encoding the Cre recombinase gene was injected into the left substantia nigra of loxP-PPARr or wild type mice. Animals were treated with high doses of methamphetamine 1-month after viral injection. Administration of AAV-Cre selectively removed PPARr in left nigra in loxP-PPARr mice but not in the wild type mice. The loxP-PPARr/AAV-Cre mice that received methamphetamine showed a significant reduction in rotarod time. In vivo voltammetry was used to examine dopamine release/clearance and at 2 months after methamphetamine injection. 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-PPARr/AAV-Cre animals. Tyrosine hydroxylase immunoreactivity was reduced in the left, compared to right, nigra and dorsal striatum in loxP-PPARr/AAV-Cre mice receiving methamphetamine. Our data suggest that a deficiency in PPARr increases vulnerability to high doses of methamphetamine. Endogenous PPARr may play an important role in reducing methamphetamine toxicity in vivo.

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