Date of Award

Fall 2020

Document Type

Open Access Dissertation

Department

Chemistry and Biochemistry

First Advisor

Parastoo Hashemi

Abstract

Histamine and serotonin are important neurochemicals that maintain crucial brain functions. Both are thought to be altered in affective and neurodegenerative disorders such as depression and Parkinson’s disease. Histamine and serotonin are thought to modulate one another but the exact relationship remains unknown and this gap in knowledge makes diagnosing and treating disorders involving the transmitters difficult. The Hashemi lab studies serotonin neurochemistry to understand serotonin’s role in psychiatric disorders. However, histamine has remained an understudied neurotransmitter due to a lack of analytical tools. In 2015 and 2016, the Hashemi lab pioneered a novel detection method utilizing fast-scan cyclic voltammetry (FSCV) for the real-time detection of histamine and serotonin in vivo. Using this method, we are able to visualize the real-time modulation of serotonin by histamine through H3 receptors. The work herein furthers our understanding of the histaminergic system in the brain and its modulation of serotonin. First, we provided a review of analytical methods for monitoring neurotransmitters in the brain (Chapter 2). Then we pharmacologically challenged various aspects of the histaminergic systems of male and female mice and show the highly conserved nature of the brain (Chapter 3). This study also revealed that female mice may have a more tightly regulated brain histamine system controlled by cycling hormones. Next, we investigated the synaptic transport mechanisms of histamine and utilized a genetically modified mouse model to rule out the contribution of the serotonin transporter towards histamine clearance (Chapter 4). After we characterized the histamine system and its clearance mechanism, we applied histamine FSCV to a chronic stress mouse model of depression (Chapter 5). We found brain histamine was elevated during chronic stress and inflammation; this has large implications given the comorbidity of psychiatric disorders and chronic inflammation. Finally, we investigated the effect of ketamine, the newly approved antidepressant and anti-inflammatory compound, on histamine transmission and subsequent serotonin modulation (Chapter 6). Collectively, this dissertation furthers our understanding of histamine and serotonin modulation and the mechanisms governing their transmission. Novel discoveries will provide necessary the insight to develop more efficient and targeted therapies for brain disorders.

Rights

© 2020, Shane N. Berger

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