Contribution of Interoceptive Processing to Drug Reward and Withdrawal Aversion

项目3：药物滥用和依赖是巨大的社会问题， 在美国，成年人超过15%。尽管最近在识别关键的 成瘾的神经生物学机制，高再犯率被认为是与大多数生物学 药物依赖的治疗方法。在这里，我们建议检查相对 未探索的作用interocepfion，身体的内部感觉，在regulafion的药物相关的冲动， 提供了一个新的概念框架，从中可能出现新的治疗策略。的总目标 CIDIA旨在阐明内感受在成瘾中的作用，项目3特别考察了 岛叶皮层用于调节药物诱导的享乐加工改变，可能提供新的 成瘾治疗的目标。这个动物项目使用了直接的岛叶皮层操纵，"沉默"的 通过对GABA的过度抑制而引起的吻侧（无颗粒）或尾侧（颗粒/颗粒异常）水肿a 激动剂蝇蕈醇，检查的因果作用，interocepfive处理：（1）直接奖励 （"欣快"）效果的d-安非他明和吗啡作为衡量大脑奖励阈值;（2） 从对这些药物的急性或慢性依赖中戒断的"致焦虑"作用， 大脑奖励阈值;（3）条件（学习）之间的关联一个新的环境配对， 急性药物奖赏或戒断厌恶，如在位置条件反射范例中测量的。如此则 动物研究补充了项目1和2的人类神经成像实验， 自我功能的破坏是否改变了享乐加工的沿着多个维度：（1）积极的 （奖励，欣快）与负面影响（厌恶，烦躁不安）;（2）从初始药物暴露的时间 （急性奖赏和急性戒断）到慢性依赖;（3）直接与条件享乐 过程;和（4）兴奋剂与阿片类药物的作用。这些实验的结果将用于 人类计划修改神经成像范例，以检查这些差异是否可以 在不同阶段的药物成瘾中观察到的。例如，实验中使用的实验范式 项目1和2的第2波取决于项目3的结果，即积极与消极的沉默， 直接/间接的负面奖励效应。重要的是，该动物模型将提供一个因果检验， 横截面人类成像结果，这是相关的性质。最后，收敛有效性 动物和人类研究都可以为临床前平台奠定基础，以检查治疗方法。

Project 3: Substance abuse and dependence are enormous societal problems, with lifetime prevalence in adults greater than 15% in the United States. Despite significant recent advances in identifying critical neurobiological mechanisms underlying addicfion, high rates of recidivism are seen with most biologically based treatments of substance dependence developed to date. Here we propose to examine the relatively unexplored role of interocepfion, the internal sense of the body, in regulafion of drug-related urges, to provide a new conceptual framework from which novel treatment strategies may emerge. The overall goal of CIDIA is to elucidate the role of interoception in addicfion, and Project 3 in particular examines the role of insular cortex for regulating drug-induced alterations in hedonic processing, potentiallv providing novel targets for addiction treatment. This animal project uses a direct insular cortex manipulation, "silencing" of rostral (agranular) or caudal (granular/dysgranular) insula through excessive inhibifion with the GABAa agonist muscimol, to examine the causal role of interocepfive processing in: (1) the direct rewarding ("euphorigenic") effects of d-amphetamine and morphine as measured by brain reward thresholds; (2) the "dysphorigenic" effects of withdrawal from acute or chronic dependence on these drugs as measured by brain reward thresholds; (3) the conditioned (learned) associafion between a novel environment paired with acute drug reward or withdrawal aversion as measured in a place conditioning paradigm. In this way, the animal study complements the human neuroimaging experiments of Projects 1 and 2 by ascertaining whether disruption of insula function alters hedonic processing along mulfiple dimensions: (1) posifive (reward, euphoria) versus negative affect (aversion, dysphoria); (2) across time from initial drug exposure (acute reward and acute withdrawal) to chronic dependence; (3) direct versus condifioned hedonic processes; and (4) stimulant versus opioid effects. The results of these experiments will be used in the human projects to modify the neuroimaging paradigms to examine whether these differences can be observed in subjects in different stages of drug addiction. For example, the experimental paradigms used in Wave 2 of Projects 1 and 2 are contingent on Project 3 outcomes of insula silencing on positive versus negative direct / indirect reward-related effects. Importantly, the animal model will provide a causal test of the cross-sectional human imaging findings, which are correlational by nature. Finally, converging validity in both animal and human studies can lay the groundwork for a pre-clinical platform to examine treatments.