Tens of thousands of adolescents and young adults have used illicit methamphetamine. This is of concern since its high-dose administration causes persistent dopaminergic deficits in adult animal models. The effects in adolescents are less studied. In adult rodents, toxic effects of methamphetamine may result partly from aberrant cytosolic dopamine accumulation and subsequent reactive oxygen species formation. The vesicular monoamine transporter-2 (VMAT-2) sequesters cytoplasmic dopamine into synaptic vesicles for storage and perhaps protection against dopamine-associated oxidative consequences. Accordingly, aberrant VMAT-2 function may contribute to the methamphetamine-induced persistent dopaminergic deficits. Hence, this study examined effects of methamphetamine on VMAT-2 in adolescent (postnatal day 40) and young adult (postnatal day 90) rats. Results revealed that high-dose methamphetamine treatment caused greater acute (within 1 h) decreases in vesicular dopamine uptake in postnatal day 90 versus 40 rats, as determined in a nonmembrane-associated subcellular fraction. Greater basal levels of VMAT-2 at postnatal day 90 versus 40 in this purified fraction seemed to contribute to the larger effect. Basal tissue dopamine content was also greater in postnatal day 90 versus 40 rats. In addition, postnatal day 90 rats were more susceptible to methamphetamine-induced persistent dopaminergic deficits as assessed by measuring VMAT-2 activity and dopamine content 7 days after treatment, even if drug doses were adjusted for age-related pharmacokinetic differences. Together, these data demonstrate dynamic changes in VMAT-2 susceptibility to methamphetamine as a function of development. Implications with regard to methamphetamine-induced dopaminergic deficits, as well as dopamine-associated neurodegenerative disorders such as Parkinson's disease, are discussed.According to the Substance Abuse and Mental Health Services Administration for 2003 (2004), 1.3% of adolescents aged 12 to 17 and 5.2% of young adults aged 18 to 25 have used illicit methamphetamine (METH) at least once in their lifetime. This is of concern because it is well established that high-dose methamphetamine administrations lead to persistent dopaminergic deficits in rodents, nonhuman primates, and humans, as determined by measuring striatal dopamine levels, tyrosine hydroxylase activity, and dopamine transporter function days to months after treatment (Koda and Gibb, 1973;Wagner et al., 1980;Bennett et al., 1998;Schmidt et al., 1985;Seiden, 1985;Wilson et al., 1996).Most studies of methamphetamine and its actions have involved adult animal models. However, given the prevalence of methamphetamine use among young people, increasing attention has focused on effects of the stimulant in adolescent animal models. For example, Cappon et al. (1997) demonstrated that multiple high-dose administrations of methamphetamine reduce striatal dopamine levels in postnatal day 60, but not postnatal day 20, rats. Similarly, this highdose methamphetamine regimen lead...

Multiple high-dose methamphetamine administrations cause long-lasting (>1 week) deficits in striatal dopaminergic neuronal function. This stimulant likewise causes rapid (within 1 h) and persistent (at least 48 h) decreases in activities of striatal: 1) dopamine transporters, as assessed in synaptosomes; and 2) vesicular monoamine transporter -2 (VMAT-2), as assessed in a non-membrane-associated (referred to herein as cytoplasmic) vesicular subcellular fraction. Importantly, not all brain areas are vulnerable to methamphetamine-induced long-lasting deficits. Similarly, the present study indicates that methamphetamine exerts differential acute effects on monoaminergic transporters according to brain region. In particular, results revealed that in the nucleus accumbens, methamphetamine rapidly, but reversibly (within 24 h), decreased plasmalemmal dopamine transporter function, without effect on plasmalemmal dopamine transporter immunoreactivity. Methamphetamine also rapidly and reversibly (within 48 h) decreased cytoplasmic VMAT-2 function in this region, with relatively little effect on cytoplasmic VMAT-2 immunoreactivity. In contrast, methamphetamine did not alter either dopamine transporter or VMAT-2 activity in the hypothalamus. Noteworthy, the nucleus accumbens and hypothalamus did not display the persistent long-lasting striatal dopamine depletions caused by the stimulant. Taken together, these data suggest that deficits in plasmalemmal and vesicular monoamine transporter activity lasting greater than 24-48 h may be linked to the long-lasting dopaminergic deficits caused by methamphetamine and appear to be region specific.

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Previous studies demonstrated that tolerance to the long-term neurotoxic effects of methamphetamine on dopamine neurons could be induced by pretreating with multiple injections of escalating doses of methamphetamine. The mechanism(s) underlying this tolerance phenomenon is unknown. Some recent studies suggested that aberrant vesicular monoamine transporter-2 (VMAT-2) and dopamine transporter function contribute to neurotoxic effects of methamphetamine. Hence, the purpose of this study was to explore the role of the VMAT-2 and dopamine transporter in the induction of tolerance to the longterm persistent dopaminergic deficits caused by methamphetamine. A second purpose was to investigate the potential role of hyperthermia and alterations in brain methamphetamine distribution in this tolerance. Results revealed that the methamphetamine pretreatment regimen attenuated both the acute methamphetamine-induced decrease in VMAT-2 function 2 h after the methamphetamine challenge administration and its resulting persistent dopamine deficits without attenuating the acute methamphetamine-induced decreases in dopamine transporter uptake. Furthermore, pretreatment with methamphetamine prior to a high-dose methamphetamine challenge administration also attenuated the acute methamphetamineinduced redistribution of VMAT-2 immunoreactivity within the nerve terminal. This protection was not due to alterations in concentration of methamphetamine in the brain because both the methamphetamine-and saline-pretreated rats had similar amounts of methamphetamine and amphetamine at 30 min to 2 h after the last methamphetamine challenge injection. In summary, these data are the first to demonstrate an association between the prevention of acute alterations in vesicular dopamine uptake and the development of tolerance to the neurotoxic effects of methamphetamine.

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