Preclinical Investigations Of Genetic Correlates Of Alcohol Use Disorder
Neuroscience and Neurobiology
Alcohol use disorder (AUD) is a common neuropsychiatric condition characterized by uncontrolled alcohol use that has serious medical and social consequences. AUD is heritable and intense work has been done to characterize its genetic basis. Preclinical studies have been critical in describing the functional significance of genes associated with AUD and have advanced our understanding of the neurobiological underpinnings of this disorder. This dissertation presents a collection of mouse studies that describe behavioral and neurochemical consequences of genetic or pharmacological manipulations of three systems genetically implicated in AUD: (i) the ZIP8 transporter, (ii) the GluK1-containing kainate receptors, and (iii) the α5-containing nicotinic acetylcholine receptors (nAChR). First, we describe disturbances in baseline behavior and increased volitional alcohol intake in animals lacking the ZIP8 transporter. We then report the effects of selective inhibition of GluK1-containing kainate receptors using LY466195 on ethanol consumption, reinforcement, and withdrawal. In the third study, we describe how disruption of α5-containing nAChR function influences adolescent ethanol and nicotine consumption, as well as adult drug intake in a sex-specific manner. Finally, we propose a framework to investigate the spontaneous manifestation of ethanol withdrawal in mice voluntarily drinking alcohol in a model with high face validity. Altogether, this body of work contributes to the current understanding of the etiology of AUD.