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: 10369745
• 负责人: Wynn Legon
• 金额: $ 62.93万
• 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/10369745
• 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; Intervention; Investigation; Learning; Measures; Methods; Modeling; Neurons; Nucleus Accumbens; Opioid; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Prefrontal Cortex; Rattus; Relapse; Research; Resolution; Saline; Self Administration; Testing; Time; Translating; Translations; Treatment Protocols; United States; Withdrawal; addiction; base; brain circuitry; craving; drug craving; male; neuroadaptation; neurochemistry; neuroregulation; opioid use disorder; pre-clinical; prevent; 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.

项目总结 阿片使用障碍(OUD)是美国的一种主要流行病，目前的药物治疗 导致约50%的复发。需要其他策略来隔离、定位和修复特定的大脑回路 牵涉到渴望和旧病复发。低强度聚焦超声(LIFU)是一种新型的无创治疗方法 神经调节，可以以高空间分辨率聚焦于大脑中的任何位置。可以使用超声波 调节特定大脑区域的活动，目前被批准用于治疗其他疾病 人类。利福用于调节特定的大脑回路，作为对成瘾的干预，目前尚不清楚。 此应用程序的目标是确定利福是否具有抗复发干预的效用 建立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质(DmPFC)。DmPFC谷氨酸能 伏隔核核心(NAcc)的投射是许多药物渴望的基础，包括阿片类药物以及 对长期戒断的渴望(“孵化”)随着时间的推移而增加。在提早取款期间，这 回路是不活跃的，刺激dmPFC的干预措施阻断了孵化效应。在后期撤资期间， 这个回路是过度活跃的，抑制会下调活动，减少渴望。我们建议使用抑制性 不同戒断时期兴奋性利福对dmPFC-NAcc神经元活动的调节作用 循环，减少对复发的渴望/易感性。在目标1中，我们将应用不同剂量的抑制和 利福对dmPFC的兴奋作用及测定dmPFC活性的神经化学标志物以及特异性 DmPFC-NAcc通路中多巴胺和谷氨酸传递的标志物。我们将检查其影响 在戒断早期或晚期急性发作，然后适应7天的治疗方案。接下来，使用7天 治疗方案，我们将研究利福在早期(目标2)和晚期(目标2)戒断时对dmPFC的影响 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，我们的总体 假说是，在早期戒断过程中，利福引起的dmPFC兴奋而不是抑制将抵消 在戒断后期，利福可引起神经元活动障碍，并阻断渴求的潜伏期。 抑制，而不是兴奋，会减少神经元的活动，阻止渴望。我们的长期目标是翻译 利福进入人体临床试验，作为OUD的抗复发干预。这个应用程序是迈向 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 证明其神经调节作用的证据。