Amphetamine and its derivatives lead to long-lasting depletion of both dopamine and serotonin when administered to rodents and nonhuman primates (85,86). METH, one of the most potent of these derivatives, leads to terminal degeneration of dopaminergic neurons in the caudate-putamen, nucleus accumbens, and neocor-tex. In contrast to MPTP, the axonal trunks and soma of SNpc and VTA neurons are spared (87). However, there have been occasional reports of METH-induced cell death in the substantia nigra (88). In general, the effects of severe METH lesioning are long lasting. There is evidence of recovery of dopaminergic innervation, depending on the METH regimen and species used (89). Despite the severe depletion of stri-atal dopamine, the motor behavioral alterations seen in rodents and nonhuman primates are subtle (90).
The neurotoxic effects of METH are dependent on the efflux of dopamine since agents that deplete dopamine or block its uptake are neuroprotective (91,92). The metabolic mechanisms underlying METH-induced neurotoxicity involve the perturbation of antioxidant enzymes such as glutathione peroxidase or catalase, leading to the formation of reactive oxygen/nitrogen species, including H2O2, superoxide, and hydroxyl radicals (93-97). The administration of antioxidant therapies or overexpression of superoxide dismutase (SOD) in transgenic mice models is neuropro-tective against METH toxicity (98,99). In addition, both glutamate receptors and nitric oxide synthase (NOS) are important to METH-induced neurotoxicity since the administration of either NMDA receptor antagonists or NOS inhibitors are also neuroprotective (100). Other factors important to METH-induced neurotoxicity include the inhibition of both tyrosine hydroxylase and DAT activity and METH-induced hyperthermia (96).
The administration of METH to adult animals has played an important role in testing the molecular and biochemical mechanisms underlying dopaminergic and serotonergic neuronal axonal degeneration, especially the role of free radicals and glutamate neurotransmission. Understanding these mechanisms has led to testing different neuroprotective therapeutic modalities. An advantage of the METH model over MPTP is that the serotonergic and dopaminergic systems can be lesioned in utero during the early stages of the development of these neurotransmitter systems. Such studies have indicated that there is a tremendous degree of architectural rearrangement that occurs within the dopaminergic and serotonergic systems of injured animals as they develop. These changes may lead to altered behavior in the adult animal (101).
In light of the toxic nature of these compounds in animals, studies in humans have suggested that abusers of METH and substituted amphetamines (including MDMA "ecstasy") may suffer from the long-lasting effects of these drugs (102,103). Specifically, these individuals may be prone to develop parkinsonism (104).
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