Center on Interoceptive Dysregulation in Addiction (CIDIA)

描述（由申请人提供）：本申请要求初步支持药物成瘾临床神经生物学转化研究探索中心（P20）。拟议中的加州大学圣地亚哥分校成瘾内感觉失调中心（CIDIA）解决了一个全球性的问题：“大脑如何调节使用的冲动？”，最初的重点是“在安非他命成瘾中，一般的内感觉系统，特别是岛叶皮层的作用是什么？”内感受包括感知身体的生理状态，在正在进行的活动背景下有意识地表达这种内部状态，以及发起有动机的行动来调节这种状态。最近的人类和动物研究结果提供了令人信服的证据，表明脑岛的内感受加工可能介导与药物相关的冲动和偏好。尽管有这些证据，人们仍然不清楚脑岛究竟是如何调节这些行为的，以及内感受处理在成瘾的不同阶段扮演什么角色。为了解决这些问题，我们提出了以下具体目标：(1)利用功能磁共振成像（fMRI）确定青少年和成人在安非他明使用/成瘾阶段的内感受系统的反应特征；(2)在啮齿类动物模型中，通过使用muscimol使神经活动可逆失活，通过“脑岛沉默”来描述内感受加工在介导直接和条件奖励或厌恶效应中的因果作用；(3)整合动物和人类研究的结果，并通过(a)建立内感受功能障碍的动物模型，(b)利用动物发现的预测来修改人类神经成像范式，以及(c)修改基于人类成像研究的动物“沉默”实验的目标结构，提供转化预测。该中心的目标是通过以下方式影响药物成瘾领域：(1)发展和完善我们对安非他明依赖以及可能的成瘾的内感受作用的理解；(2)建立翻译范式，探讨药物成瘾动物模型和人类不同阶段的内感受系统的敏感性；(3)为调节内感受系统作为治疗目标奠定基础；(4)发现涉及内感受加工的药物成瘾危险因素或表型。

DESCRIPTION (provided by applicant): This application requests initial support for an Exploratory Center for Translational Research on the Clinical Neurobiology of Drug Addiction (P20). The proposed UCSD Center on Interoceptive Dysregulation in Addiction (CIDIA) addresses the global question: "How does the brain regulate the urge to use?", with a focus initially on "What is the role of interoceptive systems in general, and insular cortex in particular, in amphetamine addiction?" Interoception comprises sensing the physiological condition of the body, the conscious representation of this internal state within the context of ongoing activities, and the initiation of motivated action to regulate this state. Recent human and animal findings provide compelling evidence that interoceptive processing in the insula may mediate drug-related urges and preferences. Despite this evidence, it remains unclear how exactly the insula modulates these behaviors and what role interoceptive processing plays in different stages of addiction. To address these questions, we propose the following Specific Aims: (1) To determine the response characteristics of the interoceptive system using functional magnetic resonance imaging (fMRI) in adolescents and adults across stages of amphetamine use/addiction; (2) To delineate the causal role of interoceptive processing in mediating direct and conditioned rewarding or aversive effects in a rodent model using "insula silencing" via reversible inactivation of neural activity with muscimol; and (3) To integrate results of animal and human studies and provide translational predictions by (a) developing animal models of interoceptive dysfunction, (b) using predictions from animal finding to modify human neuroimaging paradigms, and (c) modifying target structures of animal "silencing" experiments based on human imaging studies. The goal for the Center is to impact the field of drug addiction in the following ways: (1) To develop and refine our understanding of the role of interoception for amphetamine dependence and, possibly, for addiction at large; (2) To develop translational paradigms to probe the sensitivity of the interoceptive system in animal models of drug addiction and humans in different stages of drug addiction; (3) To lay the groundwork for modulating the interoceptive system as a target for treatment; and (4) To discover risk factors or phenotypes for drug addiction involving interoceptive processing. PUBLIC HEALTH RELEVANCE: Brain systems that sense the how you feel have recently been implicated in urge to use drugs. This center proposes to use animal experiments and human brain imaging studies to determine how these brain systems regulate the urge to use. Results from these experiments will provide (1) ways to monitor who is at high risk for developing drug addiction or who may relapse; (2) novel treatment targets for addiction.