Psychostimulant Addiction and Nutrient-sensing Neurons (PANN)

精神兴奋剂成瘾和营养感应神经元（PANN）

• 批准号: 10816287
• 负责人: KEN TARO WAKABAYASHI
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-05 至 2024-03-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10816287
• 关键词: Advanced Development; Alcohol consumption; Anatomy; Area; Behavior; Behavioral; Biological; Biosensor; Brain; Chronic; Cocaine; Cocaine Dependence; Data; Dependovirus; Development; Drug usage; Eating; Enzymes; Fiber; Future; Glucose; Hypothalamic structure; Intake; Lateral; Link; Methamphetamine; Methamphetamine dependence; Modeling; Neurons; Neurosciences; Optics; Outcome; Pharmaceutical Preparations; Photometry; Process; Public Health; Rattus; Recreation; Relapse; Research; Rewards; Role; Rural drug addiction; Self Administration; Sleep; Specificity; Stress; Symptoms; System; Time; Wakefulness; addiction; calcium indicator; designer receptors exclusively activated by designer drugs; detection of nutrient; effective intervention; energy balance; experience; experimental study; extracellular; glucose monitor; in vivo; in vivo calcium imaging; incentive salience; interest; melanin-concentrating hormone; mesolimbic system; methamphetamine effect; neurochemistry; neurotransmission; novel therapeutic intervention; pre-clinical; psychostimulant; response; stimulant dependence; tool

Cocaine and methamphetamine (meth) abuse is an urgent public health problem. While addiction involves many factors, a better understanding of the biological changes after drug use would significantly advance the development of new therapeutic strategies. There is a recent increased interest in determining how circuits that interface with the mesolimbic reward system regulates psychostimulant addiction. One such circuit are Melanin Concentrating Hormone (MCH) neurons that originate from the lateral hypothalamus. While these glucose-sensing neurons are studied primarily in energy balance, sleep-wakefulness, alcohol and food intake, there are hints that these neurons also are involved in processes underlying cocaine and meth addiction-like behavior. Our current research into the role of MCH in addiction has been hampered by a lack of neuronal specificity, and has not used preclinical self-administration approaches that consistently produce addiction-like behaviors in rats. Moreover, it has been discovered that cocaine changes brain glucose levels at a behaviorally relevant timescale, but how cocaine can change the activity of MCH neurons or their input into the mesolimbic system remains unknown. This project seeks to determine the changes in MCH neuronal activity after psychostimulant experience and link it to extracellular glucose levels in vivo (Aim 1). Experiments will determine the functional role of LH MCH neurons in regulating long access and intermittent access cocaine or meth self-administration, two approaches that produce addiction-like behavior in rats (Aim 2). This project will use state of the art neuroscience tools including optical recording of genetically encoded calcium indicators, in vivo glucose monitoring using enzyme-linked biosensors, and genetically targeted designer receptors exclusively activated by designer drugs. Using these approaches will allow us to determine whether cocaine and meth experience alters the response to psychostimulant drugs via a glucose related mechanism, and if the activity of MCH neurons regulate addiction-like symptoms. This will result in technical development and critical preliminary data for subsequent applications. Future proposals will focus on how MCH neurons impact central stress areas, contributing to addiction and relapse and determining how MCH neurons and their specific projections contribute towards basic reward-related processes like incentive salience attribution normally regulated by the mesolimbic system. Understanding the biological mechanisms underlying addiction, is an important component to developing effective interventions that can be applied both at a national and local level.

可卡因和甲基苯丙胺（冰毒）滥用是一个紧迫的公共卫生问题。虽然成瘾涉及到 许多因素，更好地了解药物使用后的生物变化将显着推进 开发新的治疗策略。最近，人们越来越感兴趣的是， 与中脑边缘奖励系统接口的电路调节精神兴奋剂成瘾。一个这样 黑色素浓集激素（MCH）神经元，起源于外侧下丘脑。 虽然这些葡萄糖感应神经元主要在能量平衡，睡眠-觉醒，酒精 和食物摄入，有迹象表明，这些神经元也参与了可卡因的潜在过程， 类似冰毒成瘾的行为我们目前对MCH在成瘾中的作用的研究受到以下因素的阻碍： 缺乏神经元特异性，并且没有使用临床前自我给药方法， 在老鼠身上产生类似成瘾的行为。此外，已经发现可卡因会改变大脑 在行为相关的时间尺度上的葡萄糖水平，但可卡因如何改变MCH的活性 神经元或其输入到中脑边缘系统仍然未知。该项目旨在确定 精神兴奋剂作用后MCH神经元活性的变化及其与细胞外葡萄糖的关系 体内水平（目标1）。实验将确定LH MCH神经元在调节长 获取和间歇获取可卡因或冰毒自我管理，两种方法， 大鼠的成瘾样行为（目的2）。该项目将使用最先进的神经科学工具，包括 遗传编码钙指示剂的光学记录，使用酶联的体内葡萄糖监测 生物传感器，以及由设计药物专门激活的基因靶向设计受体。使用 这些方法将使我们能够确定可卡因和冰毒的经验是否会改变对 精神兴奋剂药物通过葡萄糖相关机制，如果MCH神经元的活性调节 成瘾样症状这将导致技术发展和关键的初步数据， 后续应用。未来的提案将集中在MCH神经元如何影响中枢应激区， 有助于成瘾和复发，并确定MCH神经元及其特定投射 有助于基本的奖励相关过程，如激励显著性归因，通常由 中脑边缘系统了解成瘾的生物学机制，是一个重要的 这是制定可在国家和地方一级适用的有效干预措施的一个组成部分。