Methamphetamine alters vesicular monoamine transporter‐2 function and potassium‐stimulated dopamine release

Abstract

This report demonstrates that a repeated “challenge” high-dose methamphetamine (METH) injection regimen rapidly decreases striatal K+-stimulated dopamine (DA) release concurrent with decreases in both synaptosomal membrane-associated (referred to herein as membrane-associated) and previously-reported decreases in non-synaptosomal membrane-associated (presumably cytoplasmic) vesicular DA uptake and content. Resembling previously reported effects involving cytoplasmic vesicles wherein uptake was decreased 48 h after treatment, the decrease in membrane-associated uptake persisted 72 h. Cytoplasmic and membrane-associated vesicular DA uptakes were decreased 7 d after the challenge regimen. A single METH injection also rapidly decreased K+-stimulated DA release, membrane-associated DA content, and membrane-associated DA uptake; however, unlike after the challenge regimen, the decrease in uptake recovered by 24 h. Pretreatment with the D2 receptor antagonist, eticlopride, did not attenuate the decrease in membrane-associated uptake as assessed 1 h after either a single or challenge treatment. However, eticlopride attenuated the decrease in membrane-associated uptake caused by the challenge regimen as assessed 24 h later. These data reveal complex effects of METH on vesicular function that vary according to the vesicle population under study, dosing regimen, and time after treatment. These may contribute to both the decrease in K+-stimulated DA release and the persistent dopaminergic deficits caused by METH.

Biphasic dopamine regulation in mesoaccumbens pathway in response to non-contingent binge and escalating methamphetamine regimens in the Wistar rat

“…There was also a transient decrease in VMAT2 expression, indicating that MA can at least temporarily hinder DA storage capacity. Both DAT and VMAT2 are targeted by MA (Volz et al 2007;Chu et al 2010), and here it appears MA administration affects their synthesis on short and longer time periods (Figs. 6 and 7, Table 1).…”

Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms

“…These drugs also prevented reductions in DATimmunoreactivity (Albers and Sonsalla, 1995;Xu et al, 2005) and DAT activity following METH administration (Metzger et al, 2000). In addition, eticlopride attenuated the decrease in VMAT 2 caused by METH treatment (Chu et al, 2010), while raclopride attenuated METH-induced increases in GFAP in the striatum (Xu et al, 2005). Hence, pharmacological studies using D 2 -like receptor antagonists indicate a role for D 2 -like receptors in METH-induced apoptosis of striatal neurons (Xu et al, 2005) and other METH-induced toxicities.…”

The vesicular monoamine transporter 2: An underexplored pharmacological target

“…Vesicular transport is typically measured by radioactive neurotransmitter uptake into vesicles isolated from rat or mouse brain tissue. Vesicles can be prepared from animals treated with various drugs or toxicants to determine the systemic effect on uptake (29, 118–120). Alternatively, to determine pharmacokinetics, isolated vesicles from untreated animals can be treated directly with the drug or toxicant of interest.…”