Methamphetamine Rapidly Decreases Vesicular Dopamine Uptake

Brown, Jeffrey M.; Hanson, Glen R.; Fleckenstein, Annette E.

doi:10.1046/j.1471-4159.2000.0742221.x

Cited by 139 publications

(93 citation statements)

References 16 publications

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“…For example, multiple high-dose administrations of METH rapidly (within 1 h) decrease VMAT2 activity (Brown et al, 2000), an effect that may be caused by a rapid redistribution of VMAT2 to a location that is not retained in the preparation of synaptosomes (Riddle et al, 2002) and oxidation of VMAT2 (Eyerman and Yamamoto, 2007). The decrease in VMAT2 function and a loss of VMAT2 immunoreactivity persist 24 h after treatment (Eyerman and Yamamoto, 2005;Chu et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Studies involving rodents indicate there are many effects caused by repeated high-dose administrations of METH including, but not limited to, oxidative stress (for review, see Brown and Yamamoto, 2003;Krasnova and Cadet, 2009), astrocytic/microglial activation (O'Callaghan and Miller, 1994;LaVoie et al, 2004;Thomas et al, 2004), DAT complex formation (Baucum et al, 2004;Hadlock et al, 2009), and alterations in vesicular monoamine transporter 2 (VMAT2) function (Brown et al, 2000;Eyerman and Yamamoto, 2007;Guillot et al, 2008). However, the relationship among these factors has not been elucidated fully.…”

Section: Introductionmentioning

confidence: 99%

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Methamphetamine-Induced Dopamine Transporter Complex Formation and Dopaminergic Deficits: The Role of D2 Receptor Activation

Hadlock

Chu

Walters

et al. 2010

J Pharmacol Exp Ther

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Methamphetamine (METH) abuse is a serious public health issue. Of particular concern are findings that repeated highdose administrations of METH cause persistent dopaminergic deficits in rodents, nonhuman primates, and humans. Previous studies have also revealed that METH treatment causes alterations in the dopamine transporter (DAT), including the formation of higher molecular mass DAT-associated complexes. The current study extends these findings by examining mechanisms underlying DAT complex formation. The association among DAT complex formation and other METH-induced phenomena, including alterations in vesicular monoamine transporter 2 (VMAT2) immunoreactivity, astrocytic activation [as assessed by increased glial fibrillary acidic protein (GFAP) immunoreactivity], and persistent dopaminergic deficits was also explored. Results revealed that METH-induced DAT complex formation and reductions in VMAT2 immunoreactivity precede increases in GFAP immunoreactivity. Furthermore, and as reported previously for DAT complexes, pretreatment with the D2 receptor antagonist eticlopride [S-(Ϫ)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamide hydrochloride] attenuated the decrease in VMAT2 immunoreactivity as assessed 24 h after METH treatment. DAT complexes distinct from those present 24 h after METH treatment, decreases in VMAT2 immunoreactivity, and increased GFAP immunoreactivity were present 48 to 72 h after METH treatment. Pretreatment with eticlopride attenuated each of these phenomena. Finally, DAT complexes were present 7 days after METH treatment, a time point at which VMAT2 and DAT monomer immunoreactivity were also reduced. Eticlopride pretreatment attenuated each of these phenomena. These findings provide novel insight into not only receptor-mediated mechanisms underlying the effects of METH but also the interaction among factors that probably are associated with the persistent dopaminergic deficits caused by the stimulant.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Methamphetamine-Induced Dopamine Transporter Complex Formation and Dopaminergic Deficits: The Role of D2 Receptor Activation

Hadlock

Chu

Walters

et al. 2010

J Pharmacol Exp Ther

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“…Specifically, multiple highdose administrations of the dopamine-releasing agent, methamphetamine (Brown et al, 2000), or its related analog, methylenedioxymethamphetamine (Hansen et al, 2002), rapidly decrease rat striatal vesicular dopamine uptake in a non-membrane-associated (referred to herein as a cytoplasmic) vesicular preparation. The methamphetamine-induced decrease in uptake is associated with a decrease in VMAT-2 immunoreactivity in this preparation .…”

Section: Introductionmentioning

confidence: 99%

Therapeutic doses of amphetamine and methylphenidate selectively redistribute the vesicular monoamine transporter-2

Riddle

Hanson

Fleckenstein

2007

European Journal of Pharmacology

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High-dose administration of psychostimulants traffics the vesicular monoamine transporter-2 (VMAT-2), as assessed by subcellular fractionation of rat striatal tissue. This study demonstrates that administration of low doses of amphetamine or methylphenidate differentially traffic VMAT-2 within nerve terminals, with effects similar to those observed after high-dose administration. Trafficking of vesicular glutamate, acetylcholine, or GABA transporters was not altered by high-or low-dose amphetamine or methylphenidate treatment. These data represent the first report that amphetamine redistributes VMAT-2 protein. In addition, these data demonstrate that the trafficking of VMAT-2 after amphetamine or methylphenidate is selective for monoaminergic neurons.

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“…Brain dopaminergic pathways are activated by methamphetamine (Di Chiara and Imperato, 1988;Gold et al, 1989;Wise, 2002). Methamphetamine releases dopamine (DA) from synaptic vesicles into the cytosol via an interaction with the vesicular monoamine transporter (VMAT2) and by disruption of the vesicular proton gradient because of its weak basicity and high lipophilicity (Sulzer and Rayport, 1990;Pifl et al, 1995;Brown et al, 2000Brown et al, , 2001Fleckenstein et al, 2007). Subsequently, available cytosolic DA is reversetransported by the DA transporter (DAT) into the extracellular space (Sulzer et al, 1995).…”

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confidence: 99%

Lobelane Inhibits Methamphetamine-Evoked Dopamine Release via Inhibition of the Vesicular Monoamine Transporter-2

Nickell¹,

Krishnamurthy²,

Norrholm³

et al. 2009

J Pharmacol Exp Ther

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Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the lobeline molecule and determining effects on [ H]dihydrotetrabenazine binding, inhibition of [3 H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (K i ϭ 45 nM) inhibiting vesicular [ 3 H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67-and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC 50 ϭ 0.65 M; I max ϭ 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with lobeline (IC 50 ϭ 0.42 M, I max ϭ 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both transisomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for the development of a pharmacotherapeutic for methamphetamine abuse.

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Methamphetamine Rapidly Decreases Vesicular Dopamine Uptake

Cited by 139 publications

References 16 publications

Methamphetamine-Induced Dopamine Transporter Complex Formation and Dopaminergic Deficits: The Role of D2 Receptor Activation

Methamphetamine-Induced Dopamine Transporter Complex Formation and Dopaminergic Deficits: The Role of D2 Receptor Activation

Therapeutic doses of amphetamine and methylphenidate selectively redistribute the vesicular monoamine transporter-2

Lobelane Inhibits Methamphetamine-Evoked Dopamine Release via Inhibition of the Vesicular Monoamine Transporter-2

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