The neurotoxic mechanisms of amphetamine: Step by step for striatal dopamine depletion
Highlights
•A single dose of amphetamine (AMPH) in desipramine-pretreated rats was used to study the mechanism of long-lasting striatal DA depletion.
•Nicotinamide, MK-801, and cysteine all blocked AMPH-induced long-lasting striatal DA depletion.
•AMPH induced rapid loss of striatal energy and increase of striatal free radical formation.
•MK-801 blocked AMPH-induced striatal free radical formation but not rapid loss of striatal energy.
•Energy failure, excitotoxicity, and free radical formation performed consecutively to regulate AMPH-induced striatal DA 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.
