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

基本信息

批准号：
10314162
负责人：
Minna Hikaru McFarland
金额：
$ 3.75万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/10314162
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

项目摘要

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.

四氢孕酮 (ALLO) 是一种在大脑中从头产生的内源性神经类固醇，具有积极作用以及 A 型 γ-氨基丁酸 (GABAA) 受体的变构；因此，它具有抗焦虑、镇静、麻醉、抗惊厥作用。 ALLO 已成为一种有前途的治疗方法，因为它已被证明对许多精神疾病有益。拟议的研究将重点关注 ALLO 如何调节中脑边缘多巴胺传递，因为该途径的失调与许多精神疾病有关疾病，包括物质使用障碍。直接针对多巴胺传输是有问题的，因为各种副作用；因此，使用 ALLO 通过 GABAA 受体间接调节多巴胺可能被证明是更可行的行动方针。此外，ALLO 被认为比其他药物具有更好的安全性靶向 GABAA 受体，例如苯二氮卓类药物。我们实验室之前的工作表明 ALLO 剂量依赖性地减少麻醉雄性和雌性大鼠中电诱发的阶段性多巴胺释放，具有显着的性别差异。重要的是，拟议的研究将证实多巴胺的减少是否我们之前的研究中观察到的这一现象也适用于清醒大鼠的自发多巴胺瞬变。多巴胺瞬态是奖励和动机学习的关键信号，多巴胺的减少通常是被认为是厌恶的。然而，基础和临床文献表明 ALLO 并不令人厌恶，并且可以减少压力的不良后果。我提出这个提案的目的是调和这个悖论研究 ALLO 对清醒大鼠自发和提示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 动作会降低自然发生的多巴胺瞬变。由此，我预测 ALLO 会降低振幅自发的多巴胺瞬变，与我们之前的研究一致，但增加了瞬变的频率。在在巴甫洛夫调节的背景下，我预计 ALLO 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 将减少对条件反射的接近刺激（符号跟踪），但不改变无条件刺激的方法（目标跟踪）。该项目将使我能够熟练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和北卡罗来纳大学妇女情绪障碍诊所，我周围都是我可以利用的支持，成为一名多产且全面的转化科学家。总的来说，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，这一点很重要，因为它具有最近被批准用于治疗产后抑郁症。此外，药理特性 ALLO 对清醒和行为动物多巴胺传递的影响对于开发有针对性的治疗方法以改善患有各种精神疾病的患者的生活。