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

https://doi.org/10.1016/S0165-0173(01)00054-6Get rights and content

Abstract

Research into methamphetamine-induced neurotoxicity has experienced a resurgence in recent years. This is due to (1) greater understanding of the mechanisms underlying methamphetamine neurotoxicity, (2) its usefulness as a model for Parkinson’s disease and (3) an increased abuse of the substance, especially in the American Mid-West and Japan. It is suggested that the commonly used experimental one-day methamphetamine dosing regimen better models the acute overdose pathologies seen in humans, whereas chronic models are needed to accurately model human long-term abuse. Further, we suggest that these two dosing regimens will result in quite different neurochemical, neuropathological and behavioral outcomes. The relative importance of the dopamine transporter and vesicular monoamine transporter knockout is discussed and insights into oxidative mechanisms are described from observations of nNOS knockout and SOD overexpression. This review not only describes the neuropathologies associated with methamphetamine in rodents, non-human primates and human abusers, but also focuses on the more recent literature associated with reactive oxygen and nitrogen species and their contribution to neuronal death via necrosis and/or apoptosis. The effect of methamphetamine on the mitochondrial membrane potential and electron transport chain and subsequent apoptotic cascades are also emphasized. Finally, we describe potential treatments for methamphetamine abusers with reference to the time after withdrawal. We suggest that potential treatments can be divided into three categories; (1) the prevention of neurotoxicity if recidivism occurs, (2) amelioration of apoptotic cascades that may occur even in the withdrawal period and (3) treatment of the atypical depression associated with withdrawal.

Introduction

Methamphetamine (MA; N-methyl-O-phenylisopropylamine) is a cationic lipophilic molecule with potent action on the sympathetic and central nervous systems. Repetitious high-dose abuse of amphetamines (e.g., d-amphetamine (AMPH) or MA binges) result in near steady-state plasma levels and can lead to a prolonged (6–12 months) withdrawal period. This raises the question of whether neurotoxicity, or at least some long-term functional changes have led to the extended withdrawal rather than the usual, more moderate, anergia and psychoasthenia associated with stimulant withdrawal. PET imaging and post-mortem studies in humans have shown decreases in indices of dopamine (DA) function, however, more detail of MA neurotoxicity has been gleaned from animal studies. Such studies, currently are using predominantly one-day acute toxic dose (ATD) MA, have shown loss of DA and serotonin (5-HT) terminals and related pathology. The early prevailing view was that these neurotoxic effects were the result of a direct chemical insult. MA enters the terminals/neuron via the DA or 5-HT transporter (DAT and SERT, respectively) and displaces both vesicular and intracellular DA/5-HT. These displaced amines are oxidized (by MAO and auto-oxidation) to reactive oxygen species (ROS; [44], [186]), with further production of ROS via H2O2 and NO [20] resulting in necrotic cell death. However, over time other mechanisms have been added including glutamate- [131], [228] and peroxynitrite- [14] mediated neurotoxicity. Thus both reactive oxygen and nitrogen species (RONS) may be involved. It has also been shown that MA, due to its lipophilicity, can diffuse through cell membranes including intracellular organelles, for example, mitochondria, where it disrupts the electrochemical gradient. It is thus possible that MA not only kills neurons by the direct production of free radicals but also by triggering a mitochondrial-dependent induction of apoptotic cascades [188]. It appears, therefore, that MA can kill neurons by multiple mechanisms over an extended time scale (Fig. 1). Therapeutic intervention should thus be directed at these mechanisms with due regard to the time after withdrawal.

MA neurotoxicity has been reviewed previously [9], [19], [110], [155], [175], [186], [187]. The current review mainly focuses on recent progress with specific regard to: (1) laboratory models that reflect the distinction between chronic binging versus ATD; (2) the different types and time course of neurodegenerative processes; (3) possible MA-induced mechanisms of neurotoxicity; (4) necrotic versus apoptotic mechanisms; (5) discussion of short and long-term tolerance versus neurotoxic structural changes; (6) potential for preventing later apoptotic cascades and facilitating remodeling and long-term recovery and (7) issues relating to the appropriate time after withdrawal for the initiation of potential treatments.

Section snippets

Abuse patterns

Stimulant binging is characterized by frequent (every 2 h) large doses over many days and compulsive repetitive MA abuse has been described many times. Previously, and even now in Japan and in the U.S. Mid-West, ‘speed freaks’ inject compulsively (8–10 times per day) at high doses (0.3–1.0 g) daily for three to 10 days [113], [118]. The shortest t1/2 of MA is 5–6 h ranging up to 34 h [6] dependent on urine pH. Yet compulsive MA abusers are administering it at short inter-dose durations (e.g., 2

Neuropathology in humans and non-human primates

A recent post-mortem study [223] reported that chronic MA users of unknown abuse intensity had significantly decreased levels of DA, tyrosine hydroxylase (TH), and DAT (the last assessed by [3H]WIN 35428 and [3H]GBR 12935 binding and immunological staining for DAT) in the caudate and putamen. In contrast, the vesicular monoamine transporter type-2 (vMAT2) and DOPA decarboxylase levels showed no changes between controls and chronic MA abusers. The authors comment that the loss of DA nerve

Early preclinical background

The early observations by Escalante and Ellinwood [63] that chronically treated AMPH cats had neuronal chromatolysis and by Seiden et al. [185] that rhesus monkeys administered chronic high doses of MA had a depletion of caudate DA for at least 6 months afterwards, led investigators to speculate that MA was neurotoxic. Conclusive evidence of MA neurotoxicity was found by Ricaurte et al. [173], [174], who showed DA terminal destruction using silver staining; the gold-standard for demonstrating

DAT and vMAT2 knockouts have opposite effects

Fumagalli et al. [70], using ATD of MA found that tissue DA content in wild-type (Wt) was 20% of controls with no loss in DAT KO mice. Levels of the metabolites fell dramatically in both KO and Wt suggesting that the lipophilic MA can enter the terminal regardless of DAT. Regardless it may be that a fully active DAT system is needed to produce DA neurotoxicity. There was a less marked decrease in 5-HT and its metabolites. Thus the DAT may only partially contribute to 5-HT neurotoxicity. These

Mechanisms of methamphetamine neurotoxicity

As the previous section has shown there is an increasing body of evidence that MA-induced neurotoxicity is dependent upon the production of reactive species, irrespective of MA’s mode of entry into the neuron. There are three basic mechanisms by which MA administration could result in the production of such species; (1) DA release and subsequent enzymatic oxidation, (2) DA auto-oxidation and (3) mitochondrial disruption. Aberrant release of DA can also induce oxidative stress by excitatory

Effect of methamphetamine on body temperature

It has been known for some time that amphetamine-induced hyperthermia contributes to lethality in man, however, hypertensive cerebrovascular hemorrhage and cardiovascular collapse may also contribute to deaths [106], [229]. In rats temperatures may reach >40°C after each injection (e.g., [27], [28], [112], [122], [181]) where hyperthermia-induced death can occur. Chronic MA (20 mg/kg/day×7 days) by osmotic minipumps is also hyperthermic for the first 2 to 3 days, and can also result in death

Similarity to Parkinson’s disease

MA toxicity like that of MPTP is frequently cited (e.g., [196]) as a potential model of Parkinson’s disease (PD). Conversely, it may be possible to gain insight into MA pathology from PD models. Once the first sign of PD has developed, retardation of the progression of the disease should be a major goal of treatment research. The same issue in a different form applies to MA toxicity. Should MA bingers be prophylactically treated during the early withdrawal and afterwards in order to prevent

Summary

We suggest that acute toxic models of MA best represent acute overdose whereas chronic models represent the binging seen in many MA abusers. Following MA (especially chronic) treatment/abuse both short and long-term serial and parallel processes occur which result in apoptosis (Fig. 1). Further, we suggest that the MA-induced increase in extracellular glutamate promotes pathological NO synthesis with subsequent production of RONS which are the primary cause of neurotoxicity. Potential

Acknowledgements

We gratefully acknowledge funding by NIDA (DA-10327; DA-12768; DA-06519; U19 DA-109396) and the help of Dr Cindy Lazarus in preparation of this manuscript.

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