Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment

Research into methamphetamine-induced neurotoxicity has experienced a resur gence in recent years. This is due to (1) greater understanding of the mech anisms underlying methamphetamine neurotoxicity, (2) its usefulness as a mo del for Parkinson's disease and (3) an increased abuse of the substance, es pecially in the American Mid-West and Japan. It is suggested that the commo nly used experimental one-day methamphetamine dosing regimen better models the acute overdose pathologies seen in humans, whereas chronic models are n eeded to accurately model human long-term abuse. Further, we suggest that t hese two dosing regimens will result in quite different neurochemical, neur opathological and behavioral outcomes. The relative importance of the dopam ine transporter and vesicular monoamine transporter knockout is discussed a nd insights into oxidative mechanisms are described from observations of nN OS knockout and SOD overexpression. This review not only describes the neur opathologies associated with methamphetamine in rodents, non-human primates and human abusers, but also focuses on the more recent literature associat ed with reactive oxygen and nitrogen species and their contribution to neur onal death via necrosis and/or apoptosis. The effect of methamphetamine on the mitochondrial membrane potential and electron transport chain and subse quent apoptotic cascades are also emphasized. Finally, we describe potentia l treatments for methamphetamine abusers with reference to the time after w ithdrawal. We suggest that potential treatments cart be divided into three categories; (1) the prevention of neurotoxicity if recidivism occurs, (2) a melioration of apoptotic cascades that may occur even in the withdrawal per iod and (3) treatment of the atypical depression associated with withdrawal . (C) 2001 Elsevier Science B.V All rights reserved.