Role of IL-1 in Heroin's Immune and Motivational Effects

IL-1 在海洛因的免疫和激励作用中的作用

• 批准号: 8629006
• 负责人: Rita A Fuchs Lokensgard
• 金额: $ 37.58万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629006
• 关键词: Addictive Behavior; Affect; Amygdaloid structure; Behavior; Binding; Brain; Brain region; Data; Development; Dorsal; Drug Addiction; Drug abuse; Drug usage; Exhibits; Exposure to; Face; GABA Agonists; Gene Expression; Health; Heroin; Hippocampus (Brain); IL1B gene; Immune; Immune response; Immune system; Immunohistochemistry; Immunosuppression; Immunosuppressive Agents; Impairment; Infusion procedures; Interleukin-1; Interleukin-1 beta; Investigation; Label; Laboratories; Lead; Maps; Measurement; Mediating; Mediator of activation protein; Modeling; Motivation; Neuraxis; Neurons; Nucleus Accumbens; Opiates; Opioid; Peripheral; Pharmaceutical Preparations; Population; Procedures; Publishing; RNA Interference; Rattus; Recombinant Interleukin-1; Recombinant Interleukins; Research; Role; Signal Transduction; Signaling Molecule; Site; Small Interfering RNA; Stimulus; Testing; Time; Ventral Tegmental Area; base; brain cell; cell type; conditioning; cytokine; design; drug of abuse; drug relapse; drug seeking behavior; follow-up; immune function; immunoregulation; innovation; interdisciplinary approach; mRNA Expression; mind control; neural circuit; neuromechanism; novel; novel strategies; preference; prevent; protein expression; public health relevance; receptor; research study; response

Project Summary/Abstract Drugs of abuse, such as heroin, have devastating effects on immune function and lead to addictive behavior. Remarkably, these effects of heroin are conditioned to environmental stimuli. The resulting conditioned immunomodulatory and motivational effects are robust, but the neural mechanisms of these effects are poorly understood. We have made major contributions to the understanding of the neural circuitry underlying conditioned immunomodulation and motivation. Building on these findings, this R01 proposal will test the overarching hypothesis that heroin-conditioned immunomodulation and motivation to seek drug rely on altered central nervous system signaling mediated by the cytokine, interleukin-1¿ (IL-1¿). Specific Aim I will test the hypothesis that exposure to heroin-conditioned stimuli is associated with IL-1¿ expression in distinct brain regions and cell types within the CNS. We will evaluate changes in IL-1¿ expression across time in the dorsal hippocampus (DH), basolateral amygdala (BLA), nucleus accumbens shell (NACs), and ventral tegmental area (VTA), after exposure to a heroin-conditioned context or after control manipulations designed to determine whether these alterations are due to conditioning per se. We will identify specific cell types involved in these effects. As follow-up, in the brain regions that exhibit conditioned IL-1¿ expression, we will explore whether IL-1¿ is sufficient to induce immunosuppression in the absence of heroin conditioning, by examining the effects of site- specific recombinant IL-1¿ infusion. Specific Aim II will test the hypothesis that IL-1¿ gene expression is necessary in specific brain regions for the expression of heroin-conditioned immunomodulation. To demonstrate that IL-1¿ expression is necessary for heroin-conditioned immunomodulation, we will examine the effects of inhibiting IL-1¿ expression in specific brain regions on heroin-conditioned immunomodulation. IL-1¿ gene expression in the DH, BLA, NACs, or VTA will be inhibited selectively using small interfering RNA (siRNA) or the IL-1 receptor will be blocked using IL-1 receptor antagonist in the same brain regions. Specific Aim III will be to test the hypothesis that IL-1¿ gene expression in the DH is necessary for the conditioned motivational effects of a heroin-paired context that facilitate drug seeking. We will test whether IL-1¿ expression is necessary for the motivational effects of drug-paired contextual stimuli using the conditioned place preference (CPP) paradigm, given its similarity to the heroin-conditioned immunosuppression procedure. We will also evaluate whether IL-1¿ expression is necessary for drug context-induced reinstatement of heroin-seeking behavior using the contextual reinstatement paradigm, a model of drug relapse with exceptional face and predictive validity. Overall, this project takes an innovative approach to reveal novel neuroimmunological mechanisms by which drug-conditioned stimuli impact immune function and drug relapse, thereby fundamentally enhancing our understanding of the health consequences of opioid use and informing the development of novel neuroimmunological therapies to restore immune function and prevent drug relapse.

项目摘要/摘要 滥用毒品，如海洛因，会对免疫功能产生毁灭性的影响，并导致上瘾行为。 值得注意的是，海洛因的这些作用受到环境刺激的制约。由此产生的条件性 免疫调节和激励作用很强，但这些作用的神经机制很差。 明白了。我们对了解潜在的神经回路做出了重大贡献 条件性免疫调节和动力。在这些发现的基础上，R01提案将测试 最重要的假设是海洛因条件免疫调节和寻求毒品的动机依赖于改变 由细胞因子IL-1介导的中枢神经系统信号转导。具体目标我会测试一下 假设暴露在海洛因条件刺激下与IL-1？在不同的 中枢神经系统内的脑区和细胞类型。我们将评估IL-1在不同时间的表达变化 背侧海马、基底外侧杏仁核、伏隔核壳核和腹侧被盖 区域(VTA)，在暴露在海洛因条件下或在旨在确定 这些变化是否由条件反射本身引起。我们将确定这些涉及的特定细胞类型 效果。作为后续，我们将探索在大脑中表现出有条件的IL-1表达的区域，IL-1是否 在没有海洛因调理的情况下足以诱导免疫抑制，通过检查部位- 特异性重组IL-1输注。特殊目的II将检验IL-1基因表达是 在特定脑区表达海洛因条件性免疫调节所必需的。至 证明IL-1的表达是海洛因条件性免疫调节所必需的，我们将检测 抑制特定脑区IL-1表达对海洛因条件性免疫调节的影响IL-1？ 将使用小干扰RNA(SiRNA)选择性地抑制DH、BLA、NaC或VTA中的基因表达 或者在相同的脑区使用IL-1受体拮抗剂阻断IL-1受体。特定目标III将 以检验假设，即白介素1基因的表达是条件反射所必需的。 与海洛因成对的背景下促进毒品寻找的动机效应。我们将检测IL-1是否 使用条件化地点的药物配对语境刺激的动机效应需要表达 偏好(CPP)范式，因为它与海洛因条件免疫抑制程序相似。我们会 还要评估IL-1的表达是否对药物诱导的海洛因寻找的恢复是必要的 使用情境恢复范式的行为，一个具有特殊面孔和 预测效度。总体而言，这个项目采用了一种创新的方法来揭示新的神经免疫学 药物条件刺激影响免疫功能和药物复发的机制，从而从根本上 加强我们对阿片类药物使用对健康影响的认识，并为新型药物的发展提供信息 恢复免疫功能和防止药物复发的神经免疫疗法。