ReviewMethamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment
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.
References (229)
- et al.
Iron metabolism
Curr. Opin. Chem. Biol.
(1999) - et al.
Low environmental temperatures or pharmacologic agents that produce hypothermia decrease methamphetamine neurotoxicity in mice
Brain Res.
(1994) - et al.
Reliability of medial temporal lobe volume measurements using reformatted 3D images
Psychiatry Res.
(1998) - et al.
Effects of a cold environment or age on methamphetamine-induced dopamine release in the caudate putamen of female rats
Pharmacol. Biochem. Behav.
(1993) - et al.
Nitric oxide regulation of methamphetamine-induced dopamine release in caudate/putamen
Brain Res.
(1995) - et al.
Neuronal degeneration in rat forebrain resulting from d-amphetamine induced convulsions is dependent upon severity and age
Brain Res.
(1998) Neuronal degeneration in the limbic system of weanling rats exposed to saline, hyperthermia or d-amphetamine
Brain Res.
(2000)- et al.
Dithiocarbamate toxicity toward thymocytes involves their copper-catalyzed conversion to thiuram disulfides, which oxidize glutathione in a redox cycle without the release of reactive oxygen species
Arch. Biochem. Biophys.
(1998) - et al.
High-dose methamphetamine treatment alters presynaptic gaba and glutamate immunoreactivity
Neurosci.
(1999) - et al.
Free radicals and the pathobiology of brain dopamine systems
Neurochem. Int.
(1998)
Ontogeny of methamphetamine-induced neurotoxicity and associated hyperthermic response
Dev. Brain Res.
An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration
Brain Res.
Differential neurotoxicity induced by l-DOPA and dopamine in cultured striatal neurons
Brain Res.
Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide
FEBS Lett.
MK-801 reduces cerebral ischemia injury by inducing hypothermia
Brain Res.
Methamphetamine-induced neuronal damage: a possible role for free radicals
Neuropharmacology
Diethyldithiocarbanate and disulfiram inhibit MPP+ and dopamine uptake by striatal synaptosomes
Eur. J. Pharmacol.
Continuous amphetamine and cocaine have similar neurotoxic effects in lateral habenular nucleus and fasciculus retroflexus
Brain Res.
The N-methyl-d-aspartate antagonist MK-801 protects against serotonin depletions induced by methamphetamine, 3,4-methylenedioxymethamphetamine and p-chloroamphetamine
Brain Res.
Tolerance development to chronic methamphetamine intoxication in the rhesus monkey
Pharmacol. Biochem. Behav.
Differential effects of psychostimulant agents on dopaminergic and serotonergic transporter function
Eur. J. Pharmacol.
Long-term monoamine depletion, differential recovery and subtle behavioral impairment following methamphetamine-induced neurotoxicity
Pharmacol. Biochem. Behav.
Neuronal sparing and behavioral effects of the antiapoptotic drug, (−) deprenyl, following kainic acid administration
Pharmacol. Biochem. Behav.
Agonists of A1 and A2A adenosine receptors attenuate methamphetamine-induced overflow of dopamine in rat striatum
Brain Res.
Carbon dioxide enhancement of peroxynitrite-mediated protein tyrosine nitration
Arch. Biochem. Biophys.
Neuroprotective effects of the dopamine D2/D3 agonist pramipexole against postischemic or methamphetamine-induced degeneration of nigrostriatal neurons
Brain Res.
c-jun and Egr-1 participate in DNA synthesis and cell survival in response to ionizing radiation exposure
J. Biol. Chem.
[D-Ala2, D-Leu5] enkephalin blocks the methamphetamine-induced c-fos mRNA increase in mouse striatum
Eur. J. Pharmacol.
Nitric oxide, mitochondria and neurological disease
Biochem. Biophys. Acta
Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins
Brain Res. Brain Res. Rev.
Effects of dizocilpine (MK-801) on flash-evoked potentials, body temperature, and locomotor activity of hooded rats
Pharmacol. Biochem. Behav.
Autoradiographic evidence for methamphetamine-induced striatal dopaminergic loss in mouse brain; attenuation in CuZu-superoxide dismutase transgenic mice
Brain Res.
Superoxide radicals are mediators of the effects of methamphetamine on Zif268 (Egr-l, NCFI-A) in the brain: evidence from using CuZn superoxide dismutase transgenic mice
Brain Res. Mol. Brain Res.
Selenium, an antioxidant, protects against methamphetamine-induced dopaminergic neurotoxicity
Brain Res.
Selenium, an antioxidant, attenuates methamphetamine-induced dopaminergic toxicity and peroxynitrite generation
Brain Res.
Peripherally administered tetrahydrobiopterin increases in vivo tryptophan hydroxylase activity in the striatum after transplantation of fetal ventral mesencephalon in six hydroxydopamine lesioned rats
Neurosci. Lett.
Methamphetamine-induced hyperthermia and dopaminergic neurotoxicity in mice: pharmacological profile of protective and nonprotective agents
J. Pharmacol. Exp. Ther.
Methamphetamine-induced dopaminergic toxicity in mice. Role of environmental temperature and pharmacological agent
Ann. N.Y. Acad. Sci.
Neuroprotective role of melatonin in methamphetamine- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity
Ann. N.Y. Acad. Sci.
Amphetamine metabolism in amphetamine psychosis
Clin. Pharmacol. Ther.
Differential diagnosis of parkinsonism with [18F] fluorodeoxyglucose and PET
Mov. Disord.
Structural features amphetamine neurotoxicity in the brain
Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine
Br. J. Pharmacol.
Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide
Proc. Natl. Acad. Sci. USA
Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly
Am. J. Physiol.
Nitric oxide-mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases
J. Neurochem.
Regulation of mitochondrial respiration by oxygen and nitric oxide
Ann. N.Y. Acad. Sci.
The influence of environmental temperature on the transient effects of methamphetamine on dopamine levels and dopamine release in rat striatum
J. Pharmacol. Exp. Ther.
Further studies if the role of hyperthermia in methamphetamine neurotoxicity
J. Pharmacol. Exp. Ther.
Methamphetamine and amphetamine neurotoxicity
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