Contribution of Interoceptive Processing to Drug Reward and Withdrawal Aversion

内感受加工对药物奖赏和戒断厌恶的贡献

• 批准号: 7797728
• 负责人: GERHARD G SCHULTEIS
• 金额: $ 11.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797728
• 关键词: Acute; Adult; Affect; Agonist; Amphetamine Dependence; Amphetamines; Animal Model; Animals; Brain; Brain imaging; Chronic; Complement; Cues; Dependence; Development; Dextroamphetamine; Dimensions; Drug Addiction; Drug Exposure; Drug usage; Elements; Environment; Euphoria; Feeling; Goals; Human; Image; Individual; Insula of Reil; Intoxication; Journals; Learning; Lesion; Link; Maintenance; Measures; Morphine; Morphine Dependence; Muscimol; Nature; Opioid; Outcome; Pharmaceutical Preparations; Prevalence; Prevention; Procedures; Process; Property; Relapse; Reporting; Rewards; Role; Science; Signal Transduction; Staging; Stress; Structure; Substance Addiction; Substance abuse problem; System; Testing; Time; United States; Withdrawal; Withdrawal Symptom; addiction; base; body sense; conditioning; craving; drug discrimination; drug reward; drug withdrawal; dysphoria; hedonic; neural circuit; neurobiological mechanism; neuroimaging; nonmedical use; novel; pre-clinical; preference; recidivism; research study; response; treatment strategy

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.

项目 3：药物滥用和依赖是巨大的社会问题，在一生中普遍存在 美国成年人超过 15%。尽管最近在识别关键性方面取得了重大进展 成瘾背后的神经生物学机制，大多数生物学上的累犯率很高 迄今为止开发的基于物质依赖的治疗方法。在这里我们建议相对地考察一下 Interocepfion（身体的内部感觉）在调节与药物相关的冲动方面的尚未探索的作用 提供了一个新的概念框架，从中可能出现新的治疗策略。总体目标为 CIDIA 旨在阐明内感受在成瘾中的作用，项目 3 特别研究了内感受在成瘾中的作用 岛叶皮质用于调节药物引起的享乐加工改变，可能提供新的 成瘾治疗的目标。该动物项目使用直接岛叶皮层操作，“沉默” 通过 GABAa 的过度抑制，导致岛叶的喙侧（无颗粒）或尾侧（颗粒/颗粒异常） 激动剂蝇蕈醇，以检查感受间加工的因果作用：（1）直接奖励 通过大脑奖赏阈值测量的 d-安非他明和吗啡的（“欣快感”）作用； （2） 戒断对这些药物的急性或慢性依赖性的“致精神障碍”效应，通过测量 大脑奖励阈值； （3）新环境与新环境之间的条件（习得）关联 在场所条件范式中测量的急性药物奖赏或戒断厌恶。这样， 动物研究通过确定来补充项目 1 和 2 的人类神经影像实验 岛叶功能的破坏是否会改变多个维度的享乐处理：（1）积极 （奖励、欣快感）与负面情绪（厌恶、烦躁）； (2) 从初始药物暴露开始的时间跨度 （急性奖励和急性戒断）到慢性依赖； (3) 直接享乐与条件享乐 流程； (4) 兴奋剂与阿片类药物的作用。这些实验的结果将用于 人类计划修改神经影像范式，以检查这些差异是否可以被 在不同毒瘾阶段的受试者中观察到。例如，使用的实验范式 项目 1 和 2 的第二波取决于项目 3 的岛叶沉默结果 与奖励相关的直接/间接负面影响。重要的是，动物模型将提供因果检验 横截面人体成像结果，本质上是相关的。最后，收敛有效性 动物和人体研究都可以为检验治疗方法的临床前平台奠定基础。