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.

项目摘要 阿片类药物使用障碍（OUD）是美国的一种主要流行病， 导致约50%的复发。需要替代策略来隔离、定位和修复特定的大脑回路 与渴望和复发有关低强度聚焦超声（LIFU）是一种新的无创性治疗方法， 神经调节可以以高空间分辨率聚焦在大脑的任何地方。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调节特定脑回路作为成瘾干预的应用尚不清楚。 本申请的目的是确定LIFU是否可作为抗复发干预， OUD的大鼠模型，并了解其影响的神经化学机制。一 与成瘾有关的特定区域是背内侧前额叶皮层（dmPFC）。dmPFC介导的 投射到脑桥核核心（NAcc）是对许多药物的渴望的基础，包括阿片类药物，以及 依赖于时间的增加渴望（“潜伏期”）超过长期戒断。在提前退出时， 回路功能减退，激活dmPFC的干预措施会阻断潜伏效应。在延迟退出期间， 该回路是过度活跃的，抑制下调活动并减少渴望。我们建议使用抑制性 或兴奋性LIFU在不同的停药期调节神经元活动的dmPFC - NAcc 电路和减少渴望/脆弱性复发。在目标1中，我们将应用不同剂量的抑制剂， 兴奋性LIFU的dmPFC和测量神经化学标记物的dmPFC活动，以及具体的 dmPFC-NAcc通路中多巴胺和谷氨酸传递的标志物。将检查影响 在早期或晚期停药期间急性停药，然后适应7天的治疗方案。接下来，使用7天 治疗方案，我们将检查LIFU在早期（目标2）和晚期停药（目标2）期间对dmPFC的影响 3)关于复发的脆弱性。神经化学标记物也将被测量，以将大脑活动与行为联系起来。 男性和女性都将被纳入。根据以前的研究和初步数据，我们的总体 假设在早期戒断过程中，LIFU诱导的dmPFC兴奋（而非抑制）将抵消 在神经元活动的缺陷，并阻止渴望的孵化;而在晚期戒断，LIFU诱导 抑制而非兴奋会降低神经元活动并阻断渴望。我们的长期目标是翻译 LIFU作为OUD的抗复发干预进入人体临床试验。这一应用程序是一个重要的一步， 这一目标，因为结果将提供必要的临床前概念验证数据，以及初步的 神经调节作用的证据。