期刊
NEUROBIOLOGY OF DISEASE
卷 45, 期 2, 页码 810-820出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2011.11.005
关键词
Dopamine toxicity; TH; DAT; Glia; Amphetamine derivatives; Striatum; Substantia nigra; Drug-addiction; Parkinson's disease; Dopamine overflow
资金
- Spanish Ministries de Ciencia e Innovacion [BFU2008-04196]
- Sanidad y Politica Social
- ISCIII [BFU2010-20664]
- PNSD [2006/1018, 2008/074]
- RedRTA [RD06/0001/1011]
- CIBERNED
- FIS [PI070892]
- Consejeria de Educacion Ciencia y Cultura
- JCCM [PEII10-0095-872]
- INCRECyT
- CSIC
- Juan de la Cierva contract
- [SAF2007-65175]
- [RTA06/0001/0006]
Methamphetamine (METH) is a potent, highly addictive psychostimulant consumed worldwide. In humans and experimental animals, repeated exposure to this drug induces persistent neurodegenerative changes. Damage occurs primarily to dopaminergic neurons, accompanied by gliosis. The toxic effects of METH involve excessive dopamine (DA) release, thus DA receptors are highly likely to play a role in this process. To define the role of D-1 receptors in the neurotoxic effects of METH we used D-1 receptor knock-out mice (D1R-/-) and their WT littermates. Inactivation of D1R prevented METH-induced dopamine fibre loss and hyperthermia, and increases in gliosis and pro-inflammatory molecules such as iNOS in the striatum. In addition, D1R inactivation prevented METH-induced loss of dopaminergic neurons in the substantia nigra. To explore the relationship between hyperthermia and neurotoxicity, METH was given at high ambient temperature (29 degrees C). In this condition, D1R-/- mice developed hyperthermia following drug delivery and the neuroprotection provided by D1R inactivation at 23 degrees C was no longer observed. However, reserpine, which empties vesicular dopamine stores, blocked hyperthermia and strongly potentiated dopamine toxicity in D1R-/- mice, suggesting that the protection afforded by D1R inactivation is due to both hypothermia and higher stored vesicular dopamine. Moreover, electrical stimulation evoked higher DA overflow in D1R-/- mice as demonstrated by fast scan cyclic voltammetry despite their lower basal DA content, suggesting higher vesicular DA content in D1R-/- than in WT mice. Altogether, these results indicate that the D1R plays a significant role in METH-induced neurotoxicity by mediating drug-induced hyperthermia and increasing the releasable cytosolic DA pool. (C) 2011 Published by Elsevier Inc.
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