Allopregnanolone regulation of phasic dopamine release and motivated behavior

别孕酮(Allo)是一种在大脑中从头产生的内源性神经类固醇，具有积极的作用。 和变构在γ-氨基丁酸A型(GABAA)受体上；因此，它具有抗焦虑、镇静、 麻醉剂和抗惊厥作用。Allo已经成为一种有希望的治疗方法，正如它已经被证明的那样 对许多精神疾病都有好处。拟议的研究将集中在ALLO如何监管 中脑边缘多巴胺传递，因为这一途径的失调与许多精神疾病有关 包括物质使用障碍在内的障碍。直接靶向多巴胺传递是有问题的，因为 多种副作用；因此，使用Allo通过GABAA受体间接调节多巴胺可能被证明是 一个更可行的行动方案。此外，ALLO被认为比其他药物具有更好的安全性 以GABAA受体为靶标的药物，如苯二氮类药物。我们实验室之前的工作证明了Allo 剂量依赖地减少麻醉雄性和雌性大鼠电诱发的时相性多巴胺释放， 有显著的性别差异。重要的是，拟议的研究将证实多巴胺的减少 我们在之前的研究中观察到的结果延伸到清醒大鼠的自发多巴胺瞬间。多巴胺 瞬间是奖励和动机学习的关键信号，而多巴胺的减少通常是 被认为是令人厌恶的。然而，基础和临床文献表明，ALLO并不是令人厌恶的，而且可以 减少压力带来的不良后果。我这项提议的目的是调和这一悖论和 研究Allo对清醒大鼠自发和线索诱发的多巴胺释放的影响，并进一步 阐明Allo对动机行为的影响。我假设Allo动作会降低 自然产生的多巴胺瞬变。从这一点上，我预测Allo将降低 自发的多巴胺瞬变，与我们之前的研究一致，但增加了瞬变的频率。在 在巴甫洛夫条件反射的背景下，我预计Allo将减少但不会消除多巴胺的瞬变 与条件性刺激有关。此外，我预测Allo将减少对条件反射的接近 刺激(手势跟踪)，但不改变无条件刺激(目标跟踪)的方法。这个项目将 使我能够熟练掌握复杂的在体电化学技术以及统计和 动物行为训练。通过与我在鲍尔斯酒精研究中心的导师团队合作 和北卡罗来纳大学妇女情绪障碍诊所，我周围都有支持，我可以从中获得成为一名 多才多艺的翻译科学家。总体而言，这项研究将有助于该领域对 Allo对多巴胺释放和动机行为的药理作用，这一点非常重要 最近被批准用于治疗产后抑郁症。此外，对药理作用的表征 等位基因对清醒和行为动物多巴胺传递的影响 开发有针对性的治疗方法，以改善各种精神障碍患者的生活。

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.