Center on Interoceptive Dysregulation in Addiction (CIDIA)

描述（由申请人提供）： 本申请要求对药物成瘾临床神经生物学转化研究探索中心（P20）的初步支持。拟议中的UCSD成瘾内感受性失调中心（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“内感受系统，特别是岛叶皮层在安非他明成瘾中的作用是什么？“内感受包括感知身体的生理状况，在正在进行的活动的背景下对这种内部状态的有意识表示，以及启动有动机的行动来调节这种状态。最近的人类和动物的研究结果提供了令人信服的证据，内感受性处理的大脑可能介导药物相关的冲动和偏好。尽管有这些证据，但目前仍不清楚内感受性加工究竟是如何调节这些行为的，以及内感受性加工在成瘾的不同阶段扮演着什么角色。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）技术确定苯丙胺使用/成瘾各阶段青少年和成人内感受系统的反应特征;（2）在啮齿类动物模型中，采用“沉默”技术，阐明内感受性加工在介导直接和条件性奖赏或厌恶效应中的因果作用通过用蝇蕈醇可逆地灭活神经活性;和（3）整合动物和人类研究的结果，并通过（a）开发内感受性功能障碍的动物模型，（B）使用来自动物发现的预测来修改人类神经成像范例，和（c）基于人类成像研究修改动物“沉默”实验的靶结构，提供翻译预测。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性以及可能的成瘾作用的理解;（2）开发翻译范式，以探测药物成瘾动物模型和药物成瘾不同阶段人类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的危险因素或表型。 公共卫生相关性：感知你感觉如何的大脑系统最近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如何调节使用的冲动。这些实验的结果将提供（1）监测谁是发展药物成瘾的高风险或谁可能复发的方法;（2）成瘾的新治疗靶点。

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.