Ventral Pallidum Circuits Underlying Preclinical Models of Opioid Addiction

阿片类药物成瘾临床前模型的腹侧苍白球回路

• 批准号: 10587642
• 负责人: Stephen Vincent Mahler
• 金额: $ 31.9万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587642
• 关键词: Abstinence; American; Animal Model; Animals; Attention; Behavior; Behavior Disorders; Behavioral; Brain; Chronic; Cues; Dangerousness; Darkness; Data; Desire for food; Disease; Drug usage; Economics; Elasticity; Essential Drugs; Failure; Genetic; Globus Pallidus; Habenula; Half-Life; Heroin; Human; Individual; Intervention; Knowledge; Lateral; Learning; Life; Measures; Mediating; Modeling; Motivation; Neurons; Neurosciences; Occupations; Opiate Addiction; Opioid; Output; Pathway interactions; Performance; Pharmaceutical Preparations; Play; Positioning Attribute; Pre-Clinical Model; Process; Psychological reinforcement; Punishment; Rat Transgene; Rattus; Relapse; Rewards; Rodent; Rodent Model; Role; Scourge; Shock; Side; Symptoms; Testing; Ventral Tegmental Area; Withdrawal; Withdrawal Symptom; addiction; cocaine relapse; drug action; experience; fentanyl analog; gamma-Aminobutyric Acid; genetic manipulation; hedonic; heroin use; motivated behavior; neural network; novel therapeutics; opioid epidemic; opioid use disorder; preclinical study; remifentanil; segregation; stem; tool; treatment strategy

Project Summary Addiction, and opioid use disorder (OUD) in particular, is a scourge on American life. Though we know much from animal models about how opioid drugs act on the brain, we have yet to develop new OUD treatments based on this knowledge. Why is this? Our lab, like others in recent years, have argued that in part it is due to a lack of translationally-relevant rodent models that capture the key behavioral features of addiction, such as the maladaptive, compulsive, and relapsing use that develops in a subset of individuals. In humans, OUD is characterized by continued use of opioids despite negative consequences, preoccupation with using these drugs, and relapse to drug use after quitting, and for long-lasting opioids like heroin, also escalation of use, tolerance, and withdrawal. Each of these translationally-relevant behavioral phenomena can now be modelled in rodents, but the neural networks underlying each of them are yet poorly understood. The ventral pallidum (VP), and especially its dense projections to the ventral tegmental area (VTA), have drawn increasing attention for their potent roles in motivation and addiction. We recently showed VP neurons are essential for translationally-relevant cocaine relapse-like behavior, and that GABAergic VP neurons (VPGABA) and their projections to VTA are specifically responsible for a range of strongly motivated behaviors—presumably via interactions with wider neural networks of motivation. We hope that by understanding how these neural networks function during behaviors that capture key aspects of OUD, we can leverage this information to develop new neuroscience-based treatment strategies. Here, we systematically dissect the involvement of VPGABA neurons, and the wider reward and aversion networks they modulate, in OUD-relevant behaviors. In well-validated GAD1:Cre transgenic rats, we use Cre and Flp-dependent chemogenetic manipulations to show how VPGABA neurons 1) modulate wider networks underlying opioid relapse, 2) participate via their functionally-segregated outputs in appetitive aspects of OUD, and 3) how these pathways mediate aversive aspects of OUD. We hypothesize that VPGABA neurons modulate wider neural networks to generate OUD behaviors, and that inhibiting this key pathway will reduce compulsive drug seeking.

项目摘要 成瘾，特别是阿片类药物使用障碍（OUD），是美国人生活中的一个祸害。虽然我们知道很多 从阿片类药物如何作用于大脑的动物模型，我们还没有开发出新的OUD治疗方法， 在这个知识。为什么会这样呢？我们的实验室，像近年来的其他实验室一样，认为部分原因是缺乏 捕获成瘾的关键行为特征的预防性相关啮齿动物模型，例如 适应不良，强迫性和复发性使用，在一个子集的个人发展。 在人类中，OUD的特征是持续使用阿片类药物，尽管有负面后果， 使用这些药物，戒烟后复发，以及长期使用海洛因等阿片类药物， 使用、耐受和撤回的升级。每一种与预防相关的行为现象都可以 现在可以在啮齿类动物中建模，但对它们各自背后的神经网络却知之甚少。 腹侧苍白球（VP），特别是其向腹侧被盖区（VTA）的致密投射， 由于其在动机和成瘾方面的强大作用而引起越来越多的关注。我们最近展示了VP神经元 是必不可少的预防相关的可卡因复发样行为，GABA能VP神经元（VPGABA） 而他们对VTA的投射则是一系列强烈动机行为的具体原因--据推测 通过与更广泛的动机神经网络的相互作用。我们希望通过了解这些神经元 网络在捕捉OUD关键方面的行为过程中发挥作用，我们可以利用这些信息来开发 基于神经科学的新治疗策略 在这里，我们系统地剖析了VPGABA神经元的参与，以及更广泛的奖励和厌恶， 网络，他们调节，在OUD相关的行为。在经过充分验证的GAD 1：Cre转基因大鼠中，我们使用Cre 和Flp依赖的化学遗传学操作，以显示VPGABA神经元1）调节更广泛的网络 潜在的阿片类药物复发，2）通过其功能分离的输出参与OUD的食欲方面， 以及3）这些途径如何介导OUD的令人厌恶的方面。我们假设VPGABA神经元调节 更广泛的神经网络来产生OUD行为，抑制这一关键途径将减少强迫性行为。 药物寻求