Dissertation
Kinetics, zinc modulation, and glycosylation states of the dopamine transporter: effects of methamphetamine and cocaine
Washington State University
Doctor of Philosophy (PhD), Washington State University
08/2007
DOI:
https://doi.org/10.7273/000005742
Abstract
This research focuses on various molecular aspects of the dopamine transporter (DAT): In the third chapter Zn modulates dopamine (DA) transport by the human DAT (hDAT) but not the rat DAT (rDAT) expressed in human embryonic kidney cells. Zn ? reduced and increased the inhibition by cocaine in hDAT and rDAT, respectively. Zn ? and cocaine were not competitive with each other. Zn ? increased the second order binding rate constant for DA to the DAT for hDAT and rDAT. In striatal homogenates Zn ? increased dopamine transport velocity and decreased cocaine inhibition providing evidence for differences in sensitivity to Zn ? between the different preparations and also between the hDAT and rDAT.; In the fourth and fifth chapters, DAT was investigated in animals sensitized to either methamphetamine (METH) or cocaine. Effects induced by a sensitizing dose of METH on behavior, dopamine (DA) transport by the DAT, DAT density, and inhibition of DAT by METH in the nucleus accumbens (NAcc) and striatum (Str) were investigated. Changes in glycosylation of the DAT after METH sensitization were examined. Sensitization caused increased stereotypic responses in rats. Animals treated with METH, had lower and higher DAT activity in the NAcc and Str, respectively. Western blots demonstrated that DAT density was unchanged in the NAcc of METHtreated animals, but striatal DAT density decreased. The IC50 of METH increased in the NAcc and decreased in the Str. Studies using glycosidase treatments and western blots revealed that glycosylation was not affected by METH exposure. Studies examining cocaine sensitization 24 hours post treatment found that dopamine transport was decreased in the NAcc, but increased in the Str, persisting for 3 weeks after treatment. DAT density remained unchanged in both areas 24 hours post treatment, but decreased in the NAcc at 3 weeks. DAT was kinetically up-regulated in the NAcc at 3 weeks post treatment, thus the NAcc and Str may have different, but longterm alterations following treatment with cocaine.
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Details
- Title
- Kinetics, zinc modulation, and glycosylation states of the dopamine transporter
- Creators
- Nicole Lucia Bjorklund
- Contributors
- James O. Schenk (Chair)Barbara Sorg Ingermann (Committee Member) - Washington State University, Department of Integrative Physiology and NeuroscienceLisa M Gloss (Committee Member)William B Davis (Committee Member) - Washington State University, School of Molecular Biosciences
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 147
- Identifiers
- 99901054757701842
- Language
- English
- Resource Type
- Dissertation