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...