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Date of Award


Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy in Biological Sciences (PhD)

Administrative Home Department

Department of Biological Sciences

Advisor 1

Qing-Hui Chen

Committee Member 1

Jason R. Carter

Committee Member 2

Zhiying Shan

Committee Member 3

Tarun Dam


Alcohol use disorders (AUD) and alcohol associated central nervous system (CNS) pathologies, including hypertension, excitotoxicity and dependence remain a large component of excessive ethanol intake. While studies involving ethanol and the intermediate metabolite, acetaldehyde have been appreciated, very little research has been done to explore the effects of the end metabolite, acetic acid/acetate on alcohol associated CNS pathologies. As such, we explored the effects of ethanol and acetate on CNS excitatory drive through modulation of N-methyl-D-aspartate receptor (NMDAR). In study 1 we demonstrated that microinjection of ethanol and acetate in the central nucleus of amygdala (CeA) of anesthetized rats increased sympathetic nerve activity (SNA) and mean arterial pressure (MAP) which was attenuated by local NMDAR antagonists and rostral ventrolateral medulla (RVLM) knockout. In study 2 we further expanded our study, including CeA microinjected acetate, ethanol and ethanol with acetaldehyde dehydrogenase (ALDH) inhibitor on the ethanol and acetate sympathoexcitatory effect. We demonstrated that local metabolism of ethanol to acetate and NMDAR activation is the major contributor to the alcohol induced sympathoexcitatory effect. Next, we demonstrated that acetate increased CeA-RVLM neuronal excitability through activation of NMDAR and that intraneuronal acidification with acetic acid increased neuronal activity, at least in part through NMDAR modulation. In neuronal cultures incubated with low doses of acetate, we found increases in pro-inflammatory cytokines, tumor necrosis factor alpha (TNFα) and interleukin 1-beta (IL-1β), suggesting that acetate produces a CNS inflammatory effect. Overall, study 2 demonstrated that in vivo and in vitro, acetate has an excitatory effect in the CNS which may underlie numerous alcohol CNS pathologies. In study 3 we explored whether acetate was cytotoxic to dopaminergic like pheochromocytoma (PC12) cells through activation of NMDAR. We demonstrated that acetate activates NMDAR, resulting in increased cytosolic calcium and TNFα. Furthermore, acetate increased cytosolic reactive oxygen species (ROS) and apoptosis which ethanol did not. NMDAR blocker was unable to reverse acetate induced apoptosis, however it was able to abolish the influx of calcium and increases in TNFα. This suggests that acetate induced apoptosis is a result or contribution of several cellular pathways not limited to NMDAR activation alone. In study 4 we developed a method for analyzing cations, anions and acetate from liquid and tissue samples using ion chromatography. Since many CNS and peripheral pathologies give rise to electrolyte imbalance, including alcohol consumption, having an accurate method for determining these concentrations was not only crucial for alcohol metabolism, but also for a whole host of other CNS and peripheral pathologies. This study demonstrated that acetate was elevated in brain tissue relative to peripheral liver tissue, cation and anion concentrations from cerebrospinal fluid (CSF) and serum can be accurately replicated compared to alternative methodologies and that tissue electrolyte measurements can also be included through the use of one machine. Together, these studies provide new and exciting information for AUD.