4.4 Article

The neurotoxic mechanisms of amphetamine: Step by step for striatal dopamine depletion

Journal

NEUROSCIENCE LETTERS
Volume 639, Issue -, Pages 185-191

Publisher

ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2017.01.002

Keywords

Amphetamine; Striatum; Dopamine; Free radicals; Energy failure; Excitotoxicity

Categories

Funding

  1. National Bureau of Controlled Drugs, Department of Health, Taiwan, R.O.C. [DOH95-NNB-1022]
  2. Cardinal Tien Hospital, New Taipei City, Taiwan, R.O.C. [CTH105A-202]

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Amphetamine (AMPH) is a commonly abused psychostimulant that induces neuronal cell death/degeneration in humans and experimental animals. Although multiple neurotoxic mechanisms of AMPH have been intensively investigated, the interplay between these mechanisms has remained elusive. In this study, we used a rat model of AMPH-induced long-lasting striatal dopamine (DA) depletion and identified mechanisms of neurotoxicity, energy failure, excitotoxicity, and oxidative stress. Pretreatment with nicotinamide (NAM, a co-factor for the electron transport chain) blocked AMPH-induced free radical formation, energy failure, and striatal DA decrease. Also, MK-801 (a NMDA receptor antagonist) blocked AMPH-induced free radical formation and striatal DA but not energy failure decrease, indicating excitotoxicity may occur before free radical formation and after energy failure. Thus, these results show that during AMPH intoxication, energy failure, excitotoxicity, and free radical formation are orchestrated consecutively to mediate the depletion of striatal DA. (C) 2017 Elsevier Ireland Ltd. All rights reserved.

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