Methylphenidate, the vesicular monoamine transporter-2 and neurotoxicity

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Publication Type dissertation
School or College College of Pharmacy
Department Pharmacology & Toxicology
Author Sandoval, Ver©nica
Title Methylphenidate, the vesicular monoamine transporter-2 and neurotoxicity
Date 2002-05
Description It seems that multiple high-dose administrations of methamphetamine (METH) cause persistent dopamine (DA) deficits. These DA deficits are highly selective for nerve terminals in the basal ganglia system. The development of neurodegenerative disorders, such as Parkinson's disease (PD), is linked to DA deficits in nigrostriatal neurons; thus, METH-induced toxicity is frequently used as a model for PD. Several investigative groups have suggested that METH causes DA deficits because it increases intraneuronal DA levels, and subsequently causes formation of reactive oxygen species (ROS). Our laboratory and others have hypothesized that agents that decrease intraneuronal DA concentrations by increasing its sequestration within neuronal vesicles via the vesicular monoamine transporter-2 (VMAT-2) may be neuroprotective. We hypothesize that DA reuptake inhibitors, like methylphenidate (MPD), may be neuroprotective against METH-induced toxicity since vesicular DA sequestration is enhanced, thereby, decreasing intraneuronal DA and subsequent formation of ROS. Hence, this dissertation will test the hypothesis that MPD increases vesicular monoamine transport, and thereby protects against METH-induced monoaminergic toxicity. This dissertation demonstrates that MPD increased vesicular DA uptake and binding of the VMAT-2 ligand, dihydrotetrabenazine (DHTBZ), in a dose- and time-dependent manner in purified striatal vesicles prepared from treated rats. MPD treatment increased and decreased VMAT-2 immunoreactivity in striatal vesicle subcellular and plasmalemmal membrane fractions, respectively. The MPD-induced increase in both VMAT-2 immunoreactivity and DHTBZ binding was attenuated by pretreatment with either the DA D<sub>1
Type Text
Publisher University of Utah
Subject Physiology; Dopamine
Subject MESH Neurotoxins; Metanephrine
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Methylphenidate, the vesicular monoamine transporter-2 and neurotoxity." Spencer S. Eccles Health Sciences Library. Print version of "Methylphenidate, the vesicular monoamine transporter-2 and neurotoxity." available at J. Willard Marriott Library Special Collection. RM31.5 2002 .S25.
Rights Management © Ver©nica Sandoval.
Format Medium application/pdf
Format Extent 1,514,944 bytes
Identifier undthes,5408
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Funding/Fellowship NIH granats DA04222, DA00869 and DA11389 and the Gates Millennium Scholarship.
Master File Extent 1,514,971 bytes
ARK ark:/87278/s60p11x9
Setname ir_etd
ID 191884
Reference URL https://collections.lib.utah.edu/ark:/87278/s60p11x9