title: The neurotoxic mechanisms of amphetamine: Step by step for striatal dopamine depletion.
abstract: 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.
authors.affiliation: Division of Medical Research and Education, Cheng Hsin General Hospital, Taipei, Taiwan, ROC.
authors.forename: Che-Se
authors.initials: CS
authors.lastname: Tung
authors.affiliation: Department of Psychiatry, Cardinal Tien Hospital, New Taipei City, Taiwan, ROC.
authors.forename: Shang-Tang
authors.initials: ST
authors.lastname: Chang
authors.affiliation: Medical Research Center, Cardinal Tien Hospital, Hsintien, New Taipei City, Taiwan, ROC; Graduate Institute of Physiology & Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Chuen-Lin
authors.initials: CL
authors.lastname: Huang
authors.affiliation: Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC; National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan, ROC. Electronic address: andrew@nricm.edu.tw.
authors.forename: Nai-Kuei
authors.initials: NK
authors.lastname: Huang
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects*; D003913:Dextroamphetamine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D009536:Niacinamide / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley
chemical_list: D000697:Central Nervous System Stimulants; D009536:Niacinamide; D016291:Dizocilpine Maleate; D000661:Amphetamine; D003913:Dextroamphetamine; D004298:Dopamine
keywords: Amphetamine; Dopamine; Energy failure; Excitotoxicity; Free radicals; Striatum