Mechanisms underlying the reduction in alcohol intake in response to low intensity targeting of the reward circuit

奖励回路低强度目标导致酒精摄入量减少的机制

• 批准号: 10733248
• 负责人: Danielle Gulick
• 金额: $ 36.72万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733248
• 关键词: Abstinence; Acute; Adolescent; Adverse effects; Affect; Alcohol abuse; Alcohol consumption; Alcohols; Animal Model; Behavior; Behavior Therapy; Behavior assessment; Behavioral; Biomedical Engineering; Brain; Chronic; Clinical; Clinical Research; Collaborations; Corticosterone; Coupled; Data; Deep Brain Stimulation; Disease; Disulfiram; Dizziness; Drowsiness; Drug usage; Economic Burden; Elements; Ensure; Environment; Ethanol Metabolism; FDA approved; Fatigue; Female; Focused Ultrasound; Focused Ultrasound Therapy; Foundations; Goals; Health; Hypothalamic structure; Implantation procedure; Implanted Electrodes; Inpatients; Knowledge; Laws; Life; Longevity; Mechanics; Medial; Modality; Modeling; Molecular; Mus; Naltrexone; Neurologic Process; Neuronal Plasticity; Neurons; Nucleus Accumbens; Operant Conditioning; Oxidative Stress; Patients; Pattern; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Plasma; Population; Prefrontal Cortex; Process; Protocols documentation; Punishment; Reflex action; Relapse; Reporting; Research; Resolution; Rewards; Risk Factors; Role; Route; Self Administration; Sex Differences; Sleep Disorders; Stimulus; Stress; Structure; Substance Use Disorder; Surveys; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Translations; Treatment Efficacy; Treatment Side Effects; United States; Ventral Tegmental Area; Withdrawal Symptom; Work; acamprosate; addiction; alcohol abstinence; alcohol abuse therapy; alcohol availability; alcohol behavior; alcohol preferring mice; alcohol seeking behavior; alcohol sensitivity; alcohol use disorder; brain reward regions; comorbidity; compulsion; conditioned place preference; cost; craving; deprivation; disability; drinking; drug of abuse; economic cost; health economics; hemodynamics; image guided; imaging modality; in vivo; inflammatory marker; interest; male; millimeter; millisecond; negative emotional state; nervous system disorder; neural; neuroregulation; novel; novel therapeutics; optoacoustic tomography; preference; premature; prevent; reduced alcohol use; response; side effect; socioeconomics; spatiotemporal; standard care; success; tomography; ultrasound

Alcohol use disorder (AUD) remains a major issue in the United States (US) despite the various laws, campaigns, and preventative efforts. Alcohol is by far the most commonly-abused drug across the lifespan. According to 2015 data from The National Survey on Drug Use and Health, there are currently 138 million alcohol users in the US, with almost half of drinkers reporting problem drinking (binge or heavy alcohol consumption), and 15.7 million reporting an AUD. A host of pharmaceutical targets have been identified, but treatment efficacy and abstinence rates both remain low due to factors such as cost, negative physiological effects, and requirements of long-term commitment to treatment. Thus, new directions for addiction treatment are needed. In one such direction, recent advances in ultrasound technology have enabled the non-invasive modulation of deep brain systems such as the reward circuit. We propose a novel combination of low intensity focused ultrasound (LIFU) with photoacoustic tomography (PAT) localization to modify the activity of the two primary components of the reward system, the ventral tegmental area and nucleus accumbens. Our preliminary work has demonstrated that this approach reduces alcohol intake and preference when administered once daily in either region. Thus, in the proposed studies, we will examine the mechanisms by which LIFU reduces alcohol intake, the longevity of this effect, and potential side effects of this treatment on the brain. We will first optimize our protocol for maximum efficacy in the deep brain regions of the reward circuit. Next, we will assess a variety of behaviors related to affect and to alcohol-seeking in order to identify the neurological processes on which LIFU is exerting its effects. Finally, we will assess the molecular effects in the brain following LIFU treatment, in order to identify those neuronal changes that may explain the behavioral shifts, and to determine whether there are any adverse effects on neuronal function following chronic LIFU treatment. For these studies, we will use male and female crossed high-alcohol-preferring mice, in order to identify whether there are sex-dependent differences in the effects of LIFU on alcohol-seeking, or in the neuronal effects of LIFU. These studies will provide an essential foundation of knowledge for the use of LIFU to reduce AUD, and will open the door to a wide spectrum of further studies examining other substance use disorders, and use of LIFU in traditionally difficult to treat populations, such as adolescents, or for disorders commonly comorbid with AUD, such as sleep disorders.

尽管制定了各种法律、运动、 和预防工作。迄今为止，酒精是一生中最常滥用的药物。根据 2015 年全国药物使用与健康调查数据显示，目前美国有 1.38 亿饮酒者 美国，近一半的饮酒者报告存在饮酒问题（暴饮暴食或大量饮酒），15.7 百万报告澳元。已经确定了许多药物靶标，但治疗效果和 由于成本、负面生理影响和要求等因素，戒烟率仍然很低 长期致力于治疗。因此，需要新的成瘾治疗方向。在这样的一个 方向，超声技术的最新进展使得深部大脑的非侵入性调节成为可能 奖励电路等系统。我们提出了一种低强度聚焦超声 (LIFU) 的新型组合 通过光声断层扫描 (PAT) 定位来修改两个主要成分的活性 奖赏系统、腹侧被盖区和伏隔核。我们的前期工作表明 当在任一地区每天服用一次时，这种方法可以减少酒精摄入量和偏好。因此，在 拟议的研究中，我们将研究 LIFU 减少酒精摄入量的机制、这种机制的寿命 这种治疗对大脑的影响和潜在副作用。我们将首先优化我们的协议以最大化 奖励回路大脑深部区域的功效。接下来，我们将评估与以下相关的各种行为： 影响和寻求酒精，以确定 LIFU 发挥作用的神经过程。 最后，我们将评估 LIFU 治疗后大脑中的分子效应，以确定那些 神经元的变化可以解释行为的转变，并确定是否有任何不利影响 长期 LIFU 治疗后神经元功能的影响。对于这些研究，我们将使用男性和女性杂交 偏好高度酒精的小鼠，以确定酒精影响是否存在性别依赖性差异 LIFU 对酒精寻求的影响，或 LIFU 对神经元的影响。这些研究将为 使用 LIFU 降低 AUD 的知识，并将为广泛的进一步研究打开大门 检查其他物质使用障碍，以及在传统上难以治疗的人群中使用 LIFU，例如 青少年，或通常与 AUD 共存的疾病，例如睡眠障碍。