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: 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
• 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

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.

别孕烯醇酮（allopregnanolone，ALLO）是一种内源性神经甾体，在大脑中从头产生，并积极发挥作用 并且在γ-氨基丁酸A型（GABAA）受体上变构;因此，它具有抗焦虑，镇静， 麻醉和抗惊厥作用。ALLO已成为一种有前途的治疗方法，因为它已被证明， 对很多精神疾病都有好处拟议的研究将集中在ALLO如何调节 中脑边缘多巴胺传递，因为该途径中的失调与许多精神疾病相关。 包括物质使用障碍在内的疾病。直接靶向多巴胺传递是有问题的，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 更可行的行动方案此外，ALLO被认为比其他药物具有更好的安全性 靶向GABAA受体的药物，如苯二氮卓类药物。我们实验室以前的工作表明，ALLO 剂量依赖性地减少麻醉的雄性和雌性大鼠中的电诱发的阶段性多巴胺释放， 有显著的性别差异。重要的是，拟议中的研究将证实多巴胺的减少是否 在我们先前的研究中所观察到的这种现象延伸到清醒大鼠中自发的多巴胺瞬变。多巴胺 瞬变是奖励和动机学习的关键信号，多巴胺的减少通常是 被认为是令人厌恶的。然而，基础和临床文献表明，ALLO并不令人厌恶， 减少压力的不良后果。我提出这一建议的目的是调和这一矛盾， 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行为降低了 自然产生的多巴胺瞬变由此，我预测ALLO将降低 自发多巴胺瞬变，与我们先前的研究一致，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，但不是消除，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），但不改变方法的非条件刺激（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学， 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， 和妇女情绪障碍诊所，我周围的支持，我可以借鉴，成为一个 多产和全面的翻译科学家。总之，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，药理学特征 ALLO对清醒和行为动物多巴胺传递的影响对研究 发展有针对性的治疗方法，以改善各种精神疾病患者的生活。