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.

项目总结/摘要 滥用药物，如海洛因，对免疫功能有破坏性影响，并导致成瘾行为。 值得注意的是，海洛因的这些作用是受环境刺激的影响。所产生的条件 免疫调节和激励作用是强大的，但这些作用的神经机制很差 明白我们对理解大脑皮层下的神经回路做出了重大贡献。 条件免疫调节和动机。基于这些发现，R 01提案将测试 海洛因条件性免疫调节和寻求药物的动机依赖于改变的 中枢神经系统信号传导由细胞因子介导，白细胞介素-1 <$（IL-1 <$）。具体目标我将测试 假设暴露于海洛因条件刺激与IL-1的表达相关， 中枢神经系统内的脑区域和细胞类型。我们将评估IL-1表达随时间的变化， 背侧海马（DH）、基底外侧杏仁核（BLA）、背侧被盖核壳（NACs） 区域（VTA），暴露于海洛因条件环境后或控制操作后，旨在确定 这些变化是否是由于条件作用本身。我们将确定参与这些的特定细胞类型， 方面的影响.作为后续研究，我们将探索在显示条件性IL-1表达的大脑区域中，IL-1表达是否与IL-2表达相关。 在没有海洛因条件反射的情况下，通过检查部位- 特异性重组IL-1？灌注。特异性目的II将检验IL-1基因表达是 在特定的大脑区域表达海洛因条件免疫调节所必需的。到 为了证明IL-1的表达是海洛因条件性免疫调节所必需的，我们将研究 抑制特定脑区IL-1？表达对海洛因条件免疫调节的影响。IL-1 使用小干扰RNA（siRNA）选择性抑制DH、BLA、NAC或VTA中的基因表达 或者在相同的脑区域使用IL-1受体拮抗剂阻断IL-1受体。具体目标III将 为了检验假设，DH中的IL-1基因表达是条件性的 海洛因配对背景的动机效应，促进药物寻求。我们将测试IL-1 表达对于使用条件场所的药物配对情境刺激的动机效应是必要的 偏好（CPP）范例，鉴于其与海洛因条件性免疫抑制程序的相似性。我们将 同时评估IL-1 <$的表达是否是药物环境诱导的海洛因寻求复发所必需的 行为使用上下文恢复范式，一个模型的药物复吸与特殊的脸， 预测效度总的来说，该项目采取了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 提高我们对阿片类药物使用的健康后果的理解，并为开发新的 神经免疫疗法，以恢复免疫功能和防止药物复发。