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，其终生流行率为 在美国超过15%的成年人。尽管最近在识别关键字方面取得了重大进展 成瘾背后的神经生物学机制，高再犯罪率在大多数生物学上被认为是 到目前为止，基于物质依赖的治疗方法已经发展起来。在这里，我们建议检查相对 在调节与药物有关的冲动方面，体内感觉神经的作用尚未被探索。 提供了一个新的概念框架，从中可能会出现新的治疗策略。的总目标是 CIDIA将阐明内部感觉在成瘾中的作用，项目3特别研究了 岛叶皮质调节药物诱导的享乐加工变化，可能提供新的 成瘾治疗的目标。这个动物项目使用了一种直接的岛叶皮质操作，即“沉默” 嘴(无颗粒)或尾状(颗粒状/颗粒状)岛过度抑制GABAA 激动剂Muscimol，以考察五个单位间加工的因果作用：(1)直接奖赏 (2)D-苯丙胺和吗啡对大脑奖赏阈值的影响； 戒除对这些药物的急性或慢性依赖所产生的“营养不良”效应 大脑奖赏阈值；(3)与新环境配对的条件(习得)联系 急性药物奖赏或戒断厌恶在地点条件反射范式中被测量。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 脑岛功能中断是否改变了多维度的享乐加工：(1)位置 (2)从初次吸毒开始算起的时间跨度 (3)直接与条件性享乐主义 过程；以及(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式，以检查这些差异是否可以 在药物成瘾不同阶段的受试者中观察。例如，中使用的实验范例 项目1和2的第二波取决于项目3的结果：脑岛静默的积极结果与 与奖励相关的负面直接/间接影响。重要的是，动物模型将提供一个因果检验 人体横断面影像表现，本质上是相互关联的。最后，将效度收敛于 动物和人体研究都可以为临床前检查治疗方法的平台奠定基础。

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 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.