Abstract

Parkinson’s disease (PD) results from severe dopamine (DA) neuron loss within the substantia nigra pars compacta. In an effort to replace the diminished DA levels, L-dopa, the precursor of DA, is administered. Although the most commonly prescribed medication, the site(s) where L-dopa is converted to DA is not well understood. Three likely striatal sites meeting the requirement of amino acid decarboxylase presence include remaining dopaminergic neurons, serotonergic terminals, and striatal intemeurons.

Studies have shown that serotonin (5-HT) neurons are capable of DA synthesis following exogenous L-dopa administration. In addition, striatal hyperinnervation by serotonergic dorsal raphe nucleus (DRN) axon terminals occurs following prolonged DA depletion. This dissertation tests the hypothesis that the serotonergic system is the major site where DA is synthesized from exogenous L-dopa in the DA-depleted rat.

The neurotoxins 6-hydroxydopamine, 5,7-dihydroxytryptamine, and quinolinic acid were intracerebrally injected in rats to address dopaminergic terminals, serotonergic terminals, and striatal intemeurons, respectively, as possible sites of DA production from exogenous L-dopa. Using microdialysis, in vivo measurements of extracellular DA were made during 4 conditions: basal release, under DRN stimulation, basal release in the presence of administered L-dopa, and concurrent with DRN stimulation subsequent to Ldopa treatment. DA concentration in the dialysate was determined using high-performance liquid chromatography with electrochemical detection.

In this study, the hypothesis that serotonergic terminals are the major contributors to striatal DA release following exogenous L-dopa administration was tested in rats having severe, prolonged DA depletion. First, DA release was significantly increased in DAdepleted rats following DA-denervation. Stimulation of the serotonin afferents resulted in further increased DA release. Removal of the serotonergic terminals in DA-denervated rats removed the increased basal and stimulation-evoked DA release. Application of a selective serotonin reuptake inhibitor reduced the basal and stimulation-evoked DA release but not nearly as much as the DA and 5-HT-depleted animals. Basal and stimulation-evoked DA release was minimally reduced with removal of striatal intemeurons in DA-depleted rats. These results suggest that striatal DA release following exogenous L-dopa administration in rats with severe, prolonged DA depletion occurs primarily from serotonergic nerve terminals where as striatal intemeurons are only minor contributors.

LLU Discipline

Physiology

Department

Physiology

School

Graduate School

First Advisor

Michael A. Kirby

Second Advisor

Denise Bellinger

Third Advisor

John Buchlolz

Fourth Advisor

Robert P. Iacono

Fifth Advisor

George Maeda

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2002

Date (Title Page)

6-2002

Language

English

Library of Congress/MESH Subject Headings

Dopamine -- physiology; Dopamine Agents; Serotonin.

Type

Thesis

Page Count

xiv; 160

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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