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Abstract

Many current pharmacological treatments for neuropsychiatric disorders, such as anxiety, alcohol use disorder (AUDs) and depression, are limited by a delayed onset of therapeutic effects, adverse side effects, abuse potential or lack of effects in many patients. Thus, identifying novel mechanisms and targets for treatment is very important. Glyoxalase 1 (GLO1) is a ubiquitous cytosolic enzyme primarily responsible for the clearance of methylglyoxal (MG) which is a competitive partial agonist at GABA-A receptors. Previous studies have implicated GLO1 in neuropsychiatric disorders, such as anxiety and depression. Here, we sought to build on these previous studies and assess the therapeutic potential of targeting GLO1 for the treatment of anxiety and depression. Additionally, as anxiety and depression are highly comorbid with AUD, a disorder in which GABA-A receptor function is strongly implicated, we also investigated the effects of GLO1 regulation in animal models of AUD. Within the three chapters of this dissertation, genetic and pharmacological approaches were used to assess the impact of regulating GLO1 or MG concentrations in mouse models of anxiety, AUDs and depression. Chapter 2 details the investigation into the relevant neuroanatomical regions associated with GLO1 and MG regulation of anxiety-like behavior. As previous studies used ubiquitous overexpression, we sought to determine whether neuronal Glo1 overexpression was sufficient to increase anxiety-like behavior. Furthermore, since previous administration of MG had been systemic, we sought to determine if direct microinjection of MG into the basolateral amygdala (BLA) was sufficient to reduce anxiety-like behavior. As expected, we found that anatomically specific manipulations of Glo1 and MG were sufficient to induce changes in anxiety behavior. Chapter 3 explores the impact of Glo1 expression on alcohol consumption and assesses the therapeutic potential of GLO1 inhibition for the treatment of alcohol use disorders. We found that transgenic mice overexpressing Glo1 on two different genetic backgrounds showed increased voluntary ethanol consumption compared to their wild-type littermates in a mouse model of binge drinking. Conversely, transgenic Glo1 knockdown mice on a B6 background showed decreased voluntary ethanol consumption in DID. Furthermore, pharmacological GLO1 inhibition also reduced drinking in DID. Finally, Chapter 4 examines the role of GLO1 inhibition in depression-like behavior and evaluates the therapeutic potential of GLO1 inhibitors as novel fast-acting antidepressants. We found that GLO1 inhibition by either genetic knockdown or one of two structurally distinct GLO1 inhibitors reduced depression-like behavior in multiple mouse models of depression. We further found that GLO1 inhibitors may reduce depression-like behavior with subchronic (5 day) administration, suggesting GLO1 inhibitors may be fast-acting antidepressants. Together, the data presented within this dissertation strongly support a role for GLO1 inhibitors in the treatment of multiple highly comorbid psychiatric disorders.

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