The Effect of a Neuroactive Steroid Analog and an Extrasynaptic GABA[subscript A] Receptor Agonist on Ethanol Consumption and Seeking in Mice

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Ramaker, Marcia Jean
Oregon Health & Science University
Ethanol; Pregnanolone; gamma-Aminobutyric Acid; Alcohol; Isoxazoles; Alcohol-Related Disorders; Medicine and Health Sciences
thesis / dissertation description
Alcohol use disorders (AUDs) are a group of heterogenous disorders of which no single animal model can capture the entirety of the disease. This dissertation examined the effect of a neuroactive steroid (NAS) analog ganaxolone (GAN) on measures of ethanol seeking and intake across multiple procedures in male C57BL/6J mice. NAS can act at both synaptic and extrasynaptic -aminobutyric acidA (GABAA) receptors, and it is unclear if the effects of GAN on ethanol intake are due to actions at synaptic GABAA receptors, extrasynaptic GABAA receptors, or both. In order to examine how activation of extrasynaptic GABAA receptors might be contributing to alterations in ethanol intake across the different procedures, I also examined the effect of gaboxadol (THIP), a GABAA receptor agonist with preference for extrasynaptic receptors, on ethanol seeking and consumption. My hypothesis was that both GAN and THIP would alter components of ethanol seeking and consumption, indicating a role for NAS and extrasynaptic GABAA receptor activation in altering ethanol intake, and that the nucleus accumbens (NAc) shell would be a brain region contributing to this effect. In Chapter 2, a continuous-access procedure was used in order to examine the time-related effects of GAN and THIP across 24-hours of ethanol access. In this experiment, GAN promoted the onset of ethanol consumption while decreasing overall ethanol intake. THIP produced decreases in intake that were present for the first 5 hours of access, and it also increased the latency to complete the first ethanol bout. These experiments revealed interesting divergent and comparable effects between GAN and THIP, particularly during the first hours of access, suggesting that GAN was likely exerting its effects on ethanol intake via an action at both synaptic and extrasynaptic GABAA receptors. xiv In Chapter 3, the first set of studies utilized a 2-hour limited-access procedure to take advantage of the high ethanol intakes and maximal drug effects during this shorter time period. This experiment revealed a dose-dependent decrease in ethanol intake with GAN, due to a trend for a decrease in bout frequency. Consistent with the continuous-access study, THIP dose-dependently decreased ethanol intake, and this was primarily due to a decrease in bout frequency and a delay in the onset of the first ethanol bout. Additionally, Chapter 3 utilized an operant procedure, in which lever pressing and subsequent drinking were temporally separated, in order to dissect the effects of GAN and THIP on appetitive versus consummatory behavior. GAN