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）是美国和当前药物治疗的主要流行病 导致约50％的退休。需要替代策略来隔离，靶向和修复特定的脑电路 在渴望和继电器中实施。低强度集中超声（LIFU）是一种非侵入性的新方法 可以通过高空间分辨率将神经调节聚焦在大脑中的任何地方。超声可以使用 向上或向上调节特定大脑区域的活动，目前已批准用于治疗其他疾病 人类。 LIFU在调节特定脑电路作为成瘾的干预措施中的应用是未知的。 本应用的目标是确定Lifu是否具有效用为反释放干预措施 OUD的大鼠模型，并了解其作用的神经化学机制。一 成瘾中实施的特定区域是背额前额叶皮层（DMPFC）。 DMPFC谷氨酸能 对伏隔核核心（NACC）的预测是对许多药物的渴望，包括阿片类药物以及 渴望（“孵化”）对旷日持久的戒断的渴望增加（“孵化”）。在提早提取期间，这个 电路是低触发性的，干预措施激发了DMPFC阻止孵育效果。在迟到期间， 该电路是过度活跃的，抑制作用下调了活性并减少了渴望。我们建议使用抑制作用 或在不同戒断期间的兴奋性LIFU调节DMPFC中的神经元活动 电路并减少渴望/脆弱性退休。在AIM 1中，我们将应用不同剂量的抑制性和 激发DMPFC的兴奋性LIFU并测量DMPFC活性的神经化学标志物以及特定 DMPFC-NACC途径中多巴胺和谷氨酸传播的标记。将检查效果 在早期或晚期戒断期间急性，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（AIM 2）和延迟撤回期间对DMPFC的影响（AIM 3）关于救济的脆弱性。还将测量神经化学标记以将脑活动与行为联系起来。 男性和女性都将包括在内。根据先前的研究和初步数据，我们的总体 假设是，在提早撤回期间，生命引起的兴奋（而不是抑制）将抵消DMPFC 神经元活性的缺乏并阻止渴望的孵化；鉴于，在较晚撤离期间，生命引起的 抑制（但不是兴奋）会降低神经元活性并阻止渴望。我们的长期目标是翻译 LIFU进入人类临床试验，作为OUD的抗释放干预措施。该应用是迈向的主要一步 该目标由于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。