Methamphetamine (MA) is a sympathomimetic amine with potent effects on the peripheral and central nervous systems, resulting in psychomotor activation, mood elevation, anorexia, increased mental alertness, enhanced physical endurance, and hyperthermia. The mood-elevating and positive-reinforcing effects most likely contribute to the high abuse liability of this drug. Indeed, MA abuse has increased across the United States at an alarming rate since the late 1980s. MA-related emergencies have increased sixfold in the past decade and 4-5 million people in the United States now report using MA at some time in their lives (1), highlighting the urgency for research on the pharmacology and toxicity of this drug.

Preclinical studies have revealed that single or repeated administration of a high dose of MA is neurotoxic to both rodents and nonhuman primates. High doses of MA result in a long-lasting depletion of dopamine (DA) content and a decrease in the appearance of other markers associated with DA neurotransmission in the striatum (Table 1). In contrast, DA terminals outside the extrapyramidal motor system are relatively unaffected. In recent years, similar changes in the striatal DA system have been found in human MA abusers (11,12). In contrast to this selective destruction, MA administration is also associated with widespread decreases in serotonin (5-HT) terminal markers in areas including the cortex, striatum, hippocampus, amygdala, hypothalamus, thalamus, and brainstem (8,13). Because these biochemical effects have been reported to endure for months (14,15), these changes are well accepted as evidence of neurotoxicity (for review, see ref. 16). Owing to the similarity between the relatively selective destruction of the striatal DA system in Parkinson's disease and following MA administration, a majority of the research on the underlying mechanisms of MA toxicity has focused on the ability of MA to damage DA terminals. Although damage to 5-HT terminals has been thoroughly characterized, less is known about factors mediating the toxicity to the 5-HT system after MA. Therefore, a major focus of this chapter will be on mechanisms of damage to DA neurons. The differences between this damage and damage to 5-HT neurons are addressed in the last section of the chapter.

Because amphetamines produce a massive release of DA, DA itself has been implicated in mediating the long-term effects of MA neurotoxicity. There is considerable evidence that DA can produce neurotoxicity (17-19). Furthermore, inhibition of dopaminergic transmission through the inhibition of tyrosine hydroxylase (20), the blockade of transporter-mediated DA release with uptake blockers (6,20,21), and antagonism of DA receptors (22-24) all attenuate the long-term DA depletions produced by MA. However, high extracellular DA alone does not account for the toxicity of substituted amphetamines (25,26). For example, although the local perfusion of MA into the striatum produces a

From: Contemporary Clinical Neuroscience: Glutamate and Addiction Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ

Table 1

Evidence for Damage to DA and 5-HT Nerve Terminals Following MA Administration

• Flurescent swollen tyrosine hydroxylase-positive axons (3)

• Fink-Heimer silver staining (4,5)

• Decrease in tyrosine hydroxylase-immunoreactive fibers (6,7)

• Depletion of DA and 5-HT tissue concentrations (4,8-10)

marked and sustained increase in DA release, intrastriatal MA perfusion does not produce long-term depletions of striatal DA or 5-HT tissue content (25). Consequently, additional factors likely mediate MA-induced damage to brain monoaminergic systems.

Glutamate and other excitatory amino acids have been linked to a number of neurodegenerative disorders, including Huntington's disease, brain hypoxia/ischemia, and epilepsy (27,28). Glutamate also appears to mediate the toxicity produced by MA. Sonsalla et al. (29) were the first to implicate excitatory amino acids by demonstrating that an N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, blocks the decreases in tyrosine hydroxylase activity and DA tissue content after MA. Their original findings have since been extended by others using both noncompetitive and competitive NMDA receptor antagonists (30-32). Our laboratory was the first to demonstrate that MA itself, or d-amphetamine administered to iprindole-treated rats, increases the extracellular concentration of striatal glutamate measured in vivo (33,34). These results have been confirmed subsequently by others (35-37). We have recently examined the acute and long-term effects of systemic administration of MA compared to the local intrastriatal perfusion of MA. Although both routes of administration acutely increase DA release to a similar degree, only the systemic administration of MA increases extracellular concentrations of glutamate and produces lasting depletions in striatal DA content (25). These results support the hypothesis that glutamate release is obligatory in the neurotoxic cascade that follows MA administration, but the mechanisms that appear to culminate in excitotoxicity and damage the nigrostriatal DA system are still unclear.

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