Date of Award

2017

Document Type

Open Access Dissertation

Department

Chemistry and Biochemistry

Sub-Department

College of Arts and Sciences

First Advisor

Parastoo Hashemi

Abstract

Histamine and serotonin are important biogenic amines that regulate vital brain functions. These two transmitters are thoughts to be involved in neurodegenerative diseases such as Parkinson’s and Alzheimer’s and affective disorders including depression. Histamine and serotonin are believed to regulate each other but their fundamental neuromodulation mechanisms are not well understood. This lack of understanding makes brain disorders implicating these two transmitters difficult to diagnose and treat. Our lab extensively investigates the serotonergic system to understand serotonin’s neurochemistry in the brain. However, histamine is relatively understudied with respect to other biogenic amines because of an absence of suitable analytical tools. This work introduces a strategic approach to overcome this analytical challenge and investigates the real-time neuromodulation of in vivo histamine and serotonin to understand physiological functions in healthy and disease states using fast-scan cyclic voltammetry (FSCV). First, we perform a proof-of-principle study of Copper (Cu(II)) analysis to characterize the adsorption driven FSCV response. Next, we employ FSCV to develop a novel voltammetric method to selectively and sensitively monitor real-time in vivo histamine and serotonin neurotransmissions in the posterior hypothalamus (PH). This study reveals that histamine inhibits serotonin via an H3 receptor mediated process, highlighting histamine’s roles in regulating serotonin release in the brain. Following that, we examine histamine’s reuptake mechanisms via monoamine transporter proteins and demonstrate that histamine uptake mechanism is mediated by organic cation transporters.Finally, we use our novel FSCV method to monitor histamine and serotonin neurotransmissions in HIV- 1 Tg rats, which exhibit neuroinflammation, to understand impaired neurochemical mechanisms in the disease state. Collectively, this dissertation showcases a novel and robust electroanalytical strategy to simultaneously monitor in vivo histamine and serotonin neuromodulation in real time. Innovative discoveries in this systematic investigation of the histaminergic regulation of serotonin in diverse neurochemical and pathophysiological processes will pave the way towards more efficient therapies for histamine and serotonin related brain disorders.

Rights

© 2017, Srimal Aminda Samaranayake

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