Age-dependent effects of methamphetamine on VMAT-2.

Abuse of methamphetamine (METH) among adolescents and young adults is concerning since studies have demonstrated that multiple administrations of high-dose METH induce persistent dopaminergic deficits. METH has also been shown to reduce dopamine (DA) uptake by the vesicular monoamine transporter-2 (VMAT-2) and to reduce the amount of VMAT-2 protein in a purified vesicular fraction. VMAT-2 plays a critical role in the sequestration of DA in dopaminergic nerve terminals. This function is important since DA can oxidize rapidly to form highly reactive species. It is likely that disruption of this normal intracellular processing of DA contributes to oxidative sequences ultimately leading to persistent deficits. Interestingly, METH appears to be less toxic in adolescent rats compared to young adult rats. VMAT-2 is proposed to play an important role in the age-dependent difference. Since the effect of METH on the function and quantity of VMAT-2 has primarily been studied in young adult rats and since developmental changes in the dopaminergic system are reported to occur between adolescence and adulthood, it is important to determine if there is an age-dependent difference in response of VMAT-2 to METH.