Contribution of Interoceptive Processing to Drug Reward and Withdrawal Aversion

项目3：药物滥用和依赖是一个巨大的社会问题，在美国，成年人的终生患病率超过15%。尽管最近在确定成瘾的关键神经生物学机制方面取得了重大进展，但迄今为止，大多数基于物质依赖的生物学治疗方法都显示出高累犯率。在这里，我们建议研究相对未被探索的内感受作用，即身体的内部感觉，在药物相关冲动的调节中，提供一个新的概念框架，从中可能出现新的治疗策略。CIDIA的总体目标是阐明内感受在成瘾中的作用，项目3特别研究了岛叶皮层在调节药物诱导的享乐加工改变中的作用，可能为成瘾治疗提供新的靶点。这个动物项目使用直接的岛皮层操作，通过GABAa激动剂muscimol过度抑制吻侧（颗粒状）或尾侧（颗粒状/非颗粒状）岛的“沉默”，来检查内感受加工在以下方面的因果作用：(1)d-安非他明和吗啡的直接奖励（“致兴奋”）作用，由大脑奖励阈值测量；(2)由脑奖励阈值测量的急性或慢性药物依赖戒断的“摄氧不良”效应；(3)在场所条件反射范式中，新环境与急性药物奖励或戒断厌恶之间的条件（习得）关联。通过这种方式，动物研究补充了项目1和2的人类神经成像实验，确定了脑岛功能的破坏是否会在多个维度上改变享乐加工：(1)积极（奖励、愉悦）与消极（厌恶、不安）的影响；(2)从初始药物暴露（急性奖励和急性戒断）到慢性药物依赖的时间跨度；(3)直接与条件享乐过程；(4)兴奋剂对阿片类药物的影响。这些实验的结果将用于人类项目，以修改神经影像学范式，以检验这些差异是否可以在不同阶段的药物成瘾受试者中观察到。例如，项目1和2的第二波中使用的实验范式取决于项目3中岛沉默对积极或消极直接/间接奖励相关效应的结果。重要的是，动物模型将提供横断面人体成像结果的因果测试，这是相关的性质。最后，在动物和人类研究中趋同的有效性可以为临床前检查治疗的平台奠定基础。

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 addiction, 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 interoception, the internal sense of the body, in regulation 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 addiction, and Project 3 in particular examines the role of insular cortex for regulating drug-induced alterations in hedonic processing, potentially 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 inhibition with the GABAa agonist muscimol, to examine the causal role of interoceptive 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) association 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 multiple dimensions: (1) positive (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 conditioned 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.