Allopregnanolone regulation of phasic dopamine release and motivated behavior

四氢孕酮对阶段性多巴胺释放和动机行为的调节

• 批准号: 10491710
• 负责人: Minna Hikaru McFarland
• 金额: $ 3.83万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491710
• 关键词: Alcohols; Allopregnanolone; Anesthesia procedures; Anesthetics; Animals; Anti-Anxiety Agents; Anticonvulsants; Anxiety; Behavior; Behavioral; Benzodiazepines; Brain; Chronic stress; Clinic; Clinical; Complex; Conditioned Stimulus; Cues; Development; Disease; Dopamine; Dose; Drug Targeting; Electric Stimulation; Estrous Cycle; Estrus; FDA approved; Female; Follow-Up Studies; Frequencies; Functional disorder; Goals; Infusion procedures; Knowledge; Learning; Light; Literature; Major Depressive Disorder; Measurement; Measures; Mental Depression; Mental disorders; Mentors; Mood Disorders; Motivation; Motor; National Research Service Awards; Neurons; Neuropharmacology; Nucleus Accumbens; Outcome; Pathway interactions; Patients; Periodicity; Pharmacology; Phase; Post-Traumatic Stress Disorders; Postpartum Depression; Probability; Proestrus; Progesterone; Rattus; Regulation; Research; Research Personnel; Rewards; Safety; Same-sex; Scanning; Sex Differences; Signal Transduction; Site; Stimulus; Stress; Substance Use Disorder; Symptoms; Techniques; Testing; Therapeutic; Training; Ventral Tegmental Area; Woman; Work; adverse outcome; approach behavior; awake; classical conditioning; experimental study; gamma-Aminobutyric Acid; improved; in vivo; insight; male; mesolimbic system; motivated behavior; neuronal circuitry; neurosteroids; neurotransmission; novel; novel therapeutics; pre-doctoral; receptor; response; reward processing; sedative; sex cycle; side effect; statistics; targeted treatment; translational scientist; transmission process

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.

Allopregnanolone（allo）是一种内源性神经类固醇，在大脑中产生的，并积极起作用 并在γ-氨基丁酸A型（GABAA）受体下变构；因此，它具有抗焦虑，镇静剂， 麻醉和抗惊厥作用。 Allo已成为一种有前途的治疗方法 对许多精神疾病有益。拟议的研究将侧重于Allo如何调节 中唇多巴胺的传播，因为该途径中的失调与许多精神科有关 包括药物使用障碍在内的疾病。直接靶向多巴胺传播是有问题的 各种副作用；因此，使用Allo通过GABAA受体对多巴胺的间接调节可能被证明为 一个更可行的行动。此外，Allo被认为具有比其他药物更好的安全性 该靶向GABAA受体，例如苯二氮卓类药物。我们实验室的先前工作证明了Allo 剂量依赖性地降低了麻醉的雄性和雌性大鼠的电诱发的阶段性多巴胺释放， 有显着的性别差异。重要的是，拟议的研究将确认多巴胺的减少是否 这在我们先前的研究中观察到，这扩展到清醒大鼠中自发的多巴胺瞬变。多巴胺 瞬态是奖励和动机学习中的关键信号，多巴胺的减少通常是 被认为是厌恶的。但是，基本文献和临床文献表明，Allo并不厌恶，可以 减少压力的不利后果。我对此建议的目的是调和这个悖论和 研究Allo对清醒大鼠自发和提示诱发的多巴胺释放的影响，然后 阐明阿洛对动机行为的影响。我假设Allo动作降低了 天然发生的多巴胺瞬变。由此，我预测Allo将减少 自发多巴胺瞬变与我们的先前研究一致，但增加了瞬变的频率。在 我希望帕夫洛维亚调节的背景会减少但不会消除多巴胺瞬变 与条件刺激有关。此外，我预测Allo将减少对条件的方法 刺激（标志跟踪），但没有改变无条件刺激的方法（目标跟踪）。这个项目将 使我能够掌握复杂的体内电化学技术以及统计和 动物行为训练。通过与鲍尔斯酒精研究中心的导师团队合作 以及UNC女性的情绪障碍诊所，我被我的支持所包围 富有成效且全面的转化科学家。总体而言，这项研究将有助于该领域的知识 Allo对多巴胺释放和动机行为的药理作用，这很重要 最近被批准用于治疗产后抑郁症。此外，药理学的表征 Allo对清醒和行为动物多巴胺传播的影响对 开发有针对性的治疗剂，以改善各种精神疾病的患者的生活。