Allopregnanolone regulation of phasic dopamine release and motivated behavior - 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.
