Access Type

Open Access Dissertation

Date of Award

January 2013

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Tiffany A. Mathews

Abstract

The goal of the first study was to determine if a reduction in brain-derived neurotrophic factor (BDNF) levels in female mice lead to a dysregulation in their dopaminergic system. Through a series of in vivo microdialysis and slice voltammetry experiments, we have discerned that female BDNF+/- mice are hyperdopaminergic similar to their male BDNF+/- counterparts. The in vivo microdialysis method zero-net flux highlighted that female BDNF+/- mice had increased extracellular dopamine (DA) levels, while stimulated regional release by high potassium potentiated DA release from vesicular mediated depolarization. Using the complementary technique of fast scan cyclic voltammetry, electrical stimulation evoked greater release in the female BDNF+/- mice, while uptake was not different from female wildtype mice. When the psychostimulant methamphetamine was administered, female BDNF+/- mice had potentiated DA release compared to their wildtype counterparts. Taken together, the DA release impairments in female mice appears to result in a hyperdopaminergic phenotype with no concomitant alterations in DA uptake.

The aim of the second study was to characterize how lifelong reductions in BDNF affect the striatal dopaminergic system in aged BDNF+/- mice. As BDNF+/- mice aged from 3 to 18 months, their striatal dopamine dynamics, as measured by microdialysis and slice voltammetry, `normalized' with respect to time. Aged BDNF+/- mice (18 months) had elevated levels of striatal DA metabolites and decreased phasic versus tonic release of DA with time. DA levels in BDNF+/- mice were age-dependent such that low BDNF levels in early adulthood, as previously reported, led to a hyperdopaminergic state while DA dynamics in the aged BDNF+/- mice `normalized' with no overt alterations in either behavior or neurochemistry.

In the third study we developed a method using a commercially available BDD working electrode for detecting neurotransmitters from two different families with large oxidation potential differences, DA and adenosine (Ado). Hydrodynamic voltammograms were constructed for DA and Ado, and the optimal potential for detection of DA and Ado was determined to be +740 mV and +1200 mV versus a palladium reference electrode, respectively. A working potential of +840 mV was chosen and the detection range achieved with the BDD electrode for DA and Ado was from low nanomolar to high millimolar levels. To determine the practical function of the BDD electrode, tissue content was analyzed for seven monoamines and two purine molecules, which were resolved in a single run in less than 28 min. Our results demonstrate that the BDD electrode is sensitive and robust enough to detect monoamine and purine molecules from frontal cortex and striatal mouse samples.

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