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

Che-Se Tung; Shang-Tang Chang; Chuen-Lin Huang; Nai-Kuei Huang

doi:10.1016/j.neulet.2017.01.002

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

Neurosci Lett. 2017 Feb 3:639:185-191. doi: 10.1016/j.neulet.2017.01.002. Epub 2017 Jan 6.

Authors

Che-Se Tung¹, Shang-Tang Chang², Chuen-Lin Huang³, Nai-Kuei Huang⁴

Affiliations

¹ Division of Medical Research and Education, Cheng Hsin General Hospital, Taipei, Taiwan, ROC.
² Department of Psychiatry, Cardinal Tien Hospital, New Taipei City, Taiwan, ROC.
³ 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.
⁴ 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.

PMID: 28065841
DOI: 10.1016/j.neulet.2017.01.002

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.

Keywords: Amphetamine; Dopamine; Energy failure; Excitotoxicity; Free radicals; Striatum.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amphetamine / pharmacology*
Animals
Central Nervous System Stimulants / pharmacology
Corpus Striatum / drug effects*
Dextroamphetamine / pharmacology
Dizocilpine Maleate / pharmacology
Dopamine / metabolism*
Male
Neurotoxicity Syndromes / metabolism*
Niacinamide / pharmacology*
Rats, Sprague-Dawley

Substances

Central Nervous System Stimulants
Niacinamide
Dizocilpine Maleate
Amphetamine
Dextroamphetamine
Dopamine