Methamphetamine, the vesicular monoamine transporter-2, the dopamine transporter and neurotoxicity

It is well known that methamphetamine induces long-lasting striatal dopaminergic deficits. The dopamine (DA) transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2) are two major regulators of DA homeostasis in dopaminergic neurons. In addition, DAT and VMAT-2 are targets for the actions of METH. Importantly, not all brain regions containing dopaminergic terminals, including the hypothalamus and nucleus accumbens, are vulnerable to METH-induced long-term dopaminergic deficits. Accordingly, this dissertation investigated the impact of METH on DAT and VMAT-2 in these 3 different brain regions at several early time points after METH treatment. Results reveal that METH differentially affects DAT and VMAT-2 functions according to brain region under study.Previous studies from our laboratory and others have identified two different VMAT-2-containing vesicle fractions from synaptosomes: one is the non-synaptosomal membrane-associated (presumably cytoplasmic) second one is the synaptosomal membrane-associated (referred to herein as VMAT-2C and VMAT-2M, separately). Whereas considerable study has focused on VMAT-2C-associated vesicles, a second goal of this dissertation was to investigate the impact of METH on VMAT-2M-associated vesicles. The resulting data reveal complex effects of METH on vesicular function that vary according to the vesicle population, dosing regimen, and time after METH treatment.It is established that D2 receptor activation contributes to METH-induced longterm dopaminergic deficits. Several studies of methylphenidate and cocaine demonstrated the importance of D2 receptor activation in the action of these psychostimulants. Accordingly, this dissertation tests if D2 receptor activation plays a role in METH-induced decrease of the VMAT-2M function. Results reveal that inhibition of D2 receptor activation prevents METH-induced decrease in VMAT-2M activity 24, but not 1, h after treatment. These data suggest that D2 receptor activation is not involved in METH-induced rapid VMAT-2M activity decrease but may be involved in METHinduced short-term VMAT-2M activity decrease.In summary, the findings in this dissertation support the idea that rapid activity decreases persisting longer than 24 to 48 h in DAT and VMAT-2 may be linked to the METH-induced long-lasting dopaminergic deficits. Importantly, these findings also provide novel insight into the mechanism of action of METH, as well as the pharmacological regulation of DA sequestration and release.