An investigation of low-intensity focused ultrasound for addiction

低强度聚焦超声治疗成瘾的研究

• 批准号: 10579882
• 负责人: Wynn Legon
• 金额: $ 56.63万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579882
• 关键词: Acute; Address; Affect; Animal Model; Behavior; Behavioral; Brain; Brain region; Clinic; Clinical Trials; Cues; Data; Disease; Dopamine; Dose; Epidemic; Female; Fentanyl; Focused Ultrasound; Focused Ultrasound Therapy; Future; Glutamates; Goals; Human; Hyperactivity; Incubated; Intervention; Investigation; Learning; Measures; Methods; Modeling; Neurons; Nucleus Accumbens; Opioid; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Phosphorylation; Prefrontal Cortex; Rattus; Relapse; Research; Resolution; Saline; Self Administration; Testing; Time; Translating; Translations; Treatment Protocols; United States; Withdrawal; addiction; brain circuitry; craving; drug craving; male; neuroadaptation; neurochemistry; neuroregulation; opioid use disorder; pharmacologic; pre-clinical; prevent; relapse prevention; repaired; transmission process; treatment duration; ultrasound

PROJECT SUMMARY Opioid use disorder (OUD) is a major epidemic in the United States and current pharmacological treatments result in ~50% relapse. Alternative strategies are needed to isolate, target, and repair the specific brain circuits implicated in craving and relapse. Low intensity focused ultrasound (LIFU) is a new method of non-invasive neuromodulation that can be focused anywhere in the brain with high spatial resolution. Ultrasound can be used to up or down regulate activity in specific brain regions and is currently approved for treating other disorders in humans. The application of LIFU to modulate specific brain circuitry as an intervention for addiction is unknown. The goals of this application are to determine whether LIFU has utility as an anti-relapse intervention in a rat model of OUD and to learn about the neurochemical mechanisms that underlie its effects. One specific region implicated in addiction is the dorsomedial prefrontal cortex (dmPFC). dmPFC glutamatergic projections to the nucleus accumbens core (NAcc) underlie craving for many drugs, including opioids, as well as time-dependent increases in craving (“incubation”) over protracted withdrawal. During early withdrawal, this circuit is hypoactive and interventions that excite the dmPFC block the incubation effect. During late withdrawal, this circuit is hyperactive and inhibition down-regulates activity and reduces craving. We propose to use inhibitory or excitatory LIFU during the different withdrawal periods to modulate neuronal activity in the dmPFC – NAcc circuit and reduce craving/vulnerability to relapse. In Aim 1, we will apply different doses of inhibitory and excitatory LIFU to the dmPFC and measure neurochemical markers of dmPFC activity as well as specific markers for dopamine and glutamate transmission in the dmPFC-NAcc pathway. Effects will be examined acutely during early or late withdrawal, and then adapted to a 7-day treatment regimen. Next, using a 7-day treatment regime, we will examine the effect of LIFU to the dmPFC during early (Aim 2) and late withdrawal (Aim 3) on vulnerability to relapse. Neurochemical markers will also be measured to relate brain activity to behavior. Both males and females will be included. Based on previous research and preliminary data, our overall hypothesis is that during early withdrawal, LIFU-induced excitation, but not inhibition, of the dmPFC will offset deficits in neuronal activity and block the incubation of craving; whereas, during late withdrawal, LIFU-induced inhibition, but not excitation, will decrease neuronal activity and block craving. Our long-term goal is to translate LIFU into human clinical trials as an anti-relapse intervention for OUD. This application is a major step toward this goal since the results will provide the necessary preclinical proof-of-concept data, as well as preliminary evidence for its neuromodulatory effects.

项目概要 阿片类药物使用障碍 (OUD) 在美国是一种主要流行病，目前的药物治疗 导致~50%的复发。需要替代策略来隔离、瞄准和修复特定的大脑回路 与贪爱和复发有关。低强度聚焦超声（LIFU）是一种新的非侵入性检查方法 可以以高空间分辨率聚焦在大脑任何地方的神经调节。可以使用超声波 上调或下调特定大脑区域的活动，目前已被批准用于治疗其他疾病 人类。 LIFU 调节特定大脑回路作为成瘾干预措施的应用尚不清楚。 本申请的目标是确定 LIFU 是否具有作为抗复发干预措施的效用 OUD 大鼠模型，并了解其作用背后的神经化学机制。一 与成瘾有关的特定区域是背内侧前额皮质（dmPFC）。 dmPFC 谷氨酸能 对伏隔核核心（NAcc）的投射是对许多药物的渴望的基础，包括阿片类药物以及 长期戒断后，渴望会随着时间的推移而增加（“潜伏期”）。在提前提款期间，这 电路活性低下，刺激 dmPFC 的干预措施会阻止孵化效应。在延迟提款期间， 该回路非常活跃，抑制作用会下调活动并减少渴望。我们建议使用抑制 或在不同戒断期进行兴奋性 LIFU 调节 dmPFC 中的神经元活动 – NAcc 循环并减少渴望/复发的可能性。在目标 1 中，我们将应用不同剂量的抑制和 对 dmPFC 进行兴奋性 LIFU，并测量 dmPFC 活性的神经化学标记物以及特异性 dmPFC-NAcc 通路中多巴胺和谷氨酸传输的标记。将检查效果 在早期或晚期停药期间急性发作，然后适应7天的治疗方案。接下来，使用 7 天 治疗方案中，我们将检查 LIFU 在早期（目标 2）和晚期停药（目标 3）关于复发的脆弱性。还将测量神经化学标记物，以将大脑活动与行为联系起来。 男性和女性都将被包括在内。根据之前的研究和初步数据，我们总体 假设在早期戒断期间，LIFU 诱导的 dmPFC 兴奋（而非抑制）将抵消 神经元活动缺陷并阻止渴望的产生；而在后期戒断期间，LIFU 诱导的 抑制而非兴奋会减少神经元活动并阻止渴望。我们的长期目标是翻译 LIFU 作为 OUD 的抗复发干预措施进入人体临床试验。该应用程序是朝着 这一目标，因为结果将提供必要的临床前概念验证数据以及初步 其神经调节作用的证据。