Allopregnanolone regulation of phasic dopamine release and motivated behavior

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Allopregnanolone (ALLO) is an endogenous neurosteroid produced de novo in the brain and acts positively and allosterically at gamma-aminobutyric acid type A (GABAA) receptors; thus, it has anxiolytic, sedative, anesthetic, and anticonvulsant effects. ALLO has emerged as a promising therapeutic as it has been shown to be beneficial in a number of psychiatric disorders. The proposed study will focus on how ALLO regulates mesolimbic dopamine transmission, as dysregulation in this pathway is associated with a number of psychiatric disorders including substance use disorders. Targeting dopamine transmission directly is problematic due to a variety of side effects; thus, indirect modulation of dopamine via GABAA receptors using ALLO may prove to be a more viable course of action. Moreover, ALLO is considered to have a better safety profile than other drugs that target GABAA receptors, such as benzodiazepines. Previous work in our lab demonstrated that ALLO dose-dependently reduces electrically-evoked phasic dopamine release in anesthetized male and female rats, with notable sex differences. Importantly, the proposed studies will confirm whether the reduction of dopamine that was observed in our previous study extends to spontaneous dopamine transients in awake rats. Dopamine transients are a key signal in reward and motivation learning, and a reduction in dopamine is generally considered to be aversive. However, basic and clinical literature suggests that ALLO is not aversive and can reduce the adverse consequences of stress. My aim for this proposal is to reconcile this paradox and investigate the effect of ALLO on spontaneous and cue-evoked dopamine release in awake rats, and further elucidate ALLO's effect on motivated behavior. I hypothesize that ALLO actions reduce the amplitude of naturally occurring dopamine transients. From this, I predict that ALLO will reduce the amplitude of spontaneous dopamine transients, in line with our prior study, but increase the frequency of transients. In the context of Pavlovian conditioning, I expect that ALLO will reduce, but not eliminate, dopamine transients associated with conditioned stimuli. Additionally, I predict that ALLO will reduce approach to the conditioned stimulus (sign-tracking), but not alter approach to the unconditioned stimulus (goal-tracking). This project will enable me to achieve proficiency in complex, in vivo electrochemical techniques as well as statistics and animal behavioral training. By working with my team of mentors within the Bowles Center for Alcohol Studies and the UNC Women's Mood Disorders Clinic, I am surrounded by support I can draw from to become a productive and well-rounded translational scientist. Overall, this study will contribute to the field's knowledge of the pharmacological effect of ALLO on dopamine release and motivated behavior, which is important as it has recently been approved to treat post-partum depression. Moreover, characterization of the pharmacological effect of ALLO on dopamine transmission in awake and behaving animals has valuable implications for the development of targeted therapeutics to improve the lives of patients with various psychiatric disorders.