Center on Interoceptive Dysregulation in Addiction (CIDIA)

描述(由申请人提供)：本申请请求初步支持药物成瘾的临床神经生物学转化研究探索性研究中心(第20页)。加州大学圣地亚哥分校成瘾相互感觉失调中心(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“总体上，尤其是岛叶皮质，在苯丙胺成瘾中，相互感觉系统扮演什么角色？”内感包括感知身体的生理状态，在正在进行的活动中有意识地呈现这种内部状态，以及启动有动机的行动来调节这种状态。最近的人类和动物发现提供了令人信服的证据，表明脑岛的内感加工可能调节与药物有关的冲动和偏好。尽管有这些证据，但仍不清楚脑岛究竟是如何调节这些行为的，以及内感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)来确定青少年和成人在苯丙胺使用/成瘾各阶段的内感系统的反应特征；(2)通过用苍蝇酚可逆性地灭活神经活动，描述内感加工在介导直接和条件性奖赏或厌恶效应的啮齿动物模型中的因果作用；以及(3)整合动物和人类研究的结果并提供翻译预测，方法是：(A)建立动物间感觉障碍的动物模型，(B)使用动物发现的预测来修改人类神经成像范式，以及(C)基于人类成像研究修改动物“沉默”实验的靶结构。该中心的目标是通过以下方式影响药物成瘾领域：(1)发展和完善我们对内感觉在苯丙胺依赖以及可能对整个成瘾的影响中的作用的理解；(2)开发翻译范式，以探索药物成瘾动物模型和人类不同成瘾阶段中内感觉系统的敏感性；(3)为调节作为治疗靶点的内感觉系统奠定基础；以及(4)发现涉及内感觉加工的药物成瘾的危险因素或表型。 与公共健康相关：感知你感觉的大脑系统最近被认为与使用药物的冲动有关。该中心建议使用动物实验和人脑成像研究来确定这些大脑系统是如何调节使用冲动的。这些实验的结果将提供(1)监测谁是发展成毒瘾的高风险或谁可能复发的方法；(2)新的成瘾治疗目标。

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.