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: 10377949
• 负责人: KEN TARO WAKABAYASHI
• 金额: $ 23.57万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377949
• 关键词: Advanced Development; Alcohol consumption; Area; Behavior; Behavioral; Biological; Biosensor; Brain; Cocaine; Cocaine Abuse; Cocaine Dependence; Data; Development; Drug usage; Eating; Enzymes; Future; Glucose; Hypothalamic structure; Lateral; Link; Methamphetamine; Methamphetamine dependence; Neurons; Neurosciences; Optics; Pharmaceutical Preparations; Process; Public Health; Rattus; Relapse; Research; Rewards; Role; Rural drug addiction; Self Administration; Sleep; Specificity; Stress; Symptoms; System; 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; incentive salience; interest; melanin-concentrating hormone; mesolimbic system; methamphetamine abuse; 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.

滥用可卡因和甲基苯丙胺(冰毒)是一个紧迫的公共卫生问题。虽然成瘾涉及很多因素，但更好地了解吸毒后的生物学变化将大大促进新治疗策略的发展。最近，人们对确定与中脑边缘奖赏系统相互作用的回路如何调节精神刺激剂成瘾越来越感兴趣。一个这样的回路是起源于下丘脑外侧的黑色素浓缩激素(MCH)神经元。虽然这些对葡萄糖敏感的神经元主要研究能量平衡、睡眠清醒、酒精和食物摄入，但也有迹象表明，这些神经元也参与了类似可卡因和冰毒成瘾的行为过程。我们目前对MCH在成瘾中的作用的研究由于缺乏神经元特异性而受到阻碍，并且还没有使用临床前的自我给药方法来持续地在大鼠中产生成瘾样行为。此外，已发现可卡因在行为相关的时间尺度上改变大脑葡萄糖水平，但可卡因如何改变MCH神经元的活动或它们对中脑边缘系统的输入仍不清楚。该项目旨在确定精神刺激经历后MCH神经元活性的变化，并将其与体内细胞外葡萄糖水平联系起来(目标1)。实验将确定LHMCH神经元在调节长时间接触和间歇接触可卡因或冰毒自我给药中的功能作用，这两种方法会在大鼠中产生成瘾行为(目标2)。该项目将使用最先进的神经科学工具，包括对遗传编码的钙指示剂进行光学记录，使用酶连接生物传感器进行体内血糖监测，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经验是否通过与葡萄糖有关的机制改变精神刺激药物的反应，以及MCH神经元的活动是否调节成瘾样症状。这将产生技术开发和后续应用的关键初步数据。未来的提案将集中在MCH神经元如何影响中枢应激区，导致成瘾和复发，以及确定MCH神经元及其特定投射如何促进基本的奖励相关过程，如通常由中脑边缘系统调节的激励性显著归因。了解成瘾的生物学机制，是制定可在国家和地方两级应用的有效干预措施的重要组成部分。