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 海洛因等滥用药物对免疫功能有毁灭性的影响，并导致加性行为。 值得注意的是，海洛因的这些作用是为了环境刺激的条件。由此产生的条件 免疫调节和动机作用是强大的，但是这些作用的神经力学很差 理解。我们为理解基础神经电路做出了重大贡献 有条件的免疫调节和动机。在这些发现的基础上，此R01提案将测试 总体假设，即海洛因条件的免疫调节和寻求毒品的动机依赖于改变 中枢神经系统信号传导由细胞因子介导的白介素1（IL-1？）。具体目的我将测试 假设暴露于海洛因条件的刺激与IL-1表达有关 中枢神经系统内的大脑区域和细胞类型。我们将评估IL-1表达的变化，随着时间的流逝 背侧海马（DH），基底外侧杏仁核（BLA），伏隔壳（NACS）和腹侧段 区域（VTA），暴露于海洛因条件的上下文或旨在确定的控制操作后 这些改变是否是由于条件本身。我们将确定这些涉及的特定细胞类型 效果。作为随访，在暴露于条件IL-1表达的大脑区域中，我们将探讨IL-1？是否是否 通过检查部位的影响，足以在没有海洛因调节的情况下诱导免疫抑制 特定的重组IL-1？输注。具体目标II将检验以下假设：IL-1？基因表达是 在特定的大脑区域中，需要表达海洛因调节的免疫调节。到 证明IL-1？表达是海洛因调节的免疫调节所必需的，我们将检查 在特定大脑区域抑制IL-1表达对海洛因条件的免疫调节的影响。 IL-1？ DH，BLA，NACS或VTA中的基因表达将使用小的干扰RNA（siRNA）选择性抑制 或使用同一大脑区域的IL-1受体拮抗剂阻断IL-1受体。特定的目标III将 要检验以下假设：DH中必须使用IL-1？基因表达 促进药物寻求药物的情况下的海洛因生态的动机作用。我们将测试是否IL-1？ 表达对于使用条件位置的药物配对上下文刺激的动机作用是必要的 鉴于其与海洛因条件的免疫抑制程序相似的偏好（CPP）范式。我们将 还评估IL-1？是否表达对药物上下文引起的海洛因寻求恢复是必需的 使用上下文恢复范式的行为，这是一种具有特殊面部的药物继电器模型 预测有效性。总体而言，该项目采用一种创新的方法来揭示新型的神经免疫学 药物条件刺激会影响免疫功能和药物释放的机制，从而从根本上讲 增强我们对阿片类药物使用的健康后果的理解，并告知新颖的发展 神经免疫疗法恢复免疫功能并防止药物释放。