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: 9016521
• 负责人: Rita A Fuchs Lokensgard
• 金额: $ 37.18万
• 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/9016521
• 关键词: Addictive Behavior; Affect; Amygdaloid structure; Behavior; Binding; Brain; Brain region; Conditioned Reflex; 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; 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; opioid use; preference; prevent; protein expression; receptor; research study; response

DESCRIPTION (provided by applicant): 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-1beta (IL-1beta). Specific Aim I will test the hypothesis that exposure to heroin-conditioned stimuli is associated with IL-1beta expression in distinct brain regions and cell types within the CNS. We will evaluate changes in IL-1beta 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-1beta expression, we will explore whether IL-1beta is sufficient to induce immunosuppression in the absence of heroin conditioning, by examining the effects of site-specific recombinant IL-1beta infusion. Specific Aim II will test the hypothesis that IL-1beta gene expression is necessary in specific brain regions for the expression of heroin-conditioned immunomodulation. To demonstrate that IL-1beta expression is necessary for heroin-conditioned immunomodulation, we will examine the effects of inhibiting IL-1beta expression in specific brain regions on heroin-conditioned immunomodulation. IL-1beta 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-1beta 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-1beta 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-1beta 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.

描述（由申请人提供）：滥用药物，例如海洛因，对免疫功能具有破坏性影响并导致成瘾行为。值得注意的是，海洛因的这些作用取决于环境刺激。由此产生的条件性免疫调节和激励作用是强大的，但这些作用的神经机制却知之甚少。我们为理解条件免疫调节和动机背后的神经回路做出了重大贡献。基于这些发现，这项 R01 提案将检验一个总体假设，即海洛因条件性免疫调节和寻求药物的动机依赖于细胞因子白细胞介素 1β (IL-1β) 介导的中枢神经系统信号传导的改变。具体目标 我将检验以下假设：暴露于海洛因条件刺激与中枢神经系统内不同大脑区域和细胞类型中 IL-1β 的表达相关。我们将评估在暴露于海洛因条件环境后或在旨在确定这些变化是否是由于条件反射本身的控制操作之后，背侧海马（DH）、基底外侧杏仁核（BLA）、伏隔核壳（NAC）和腹侧被盖区（VTA）中IL-1β表达随时间的变化。我们将确定参与这些效应的特定细胞类型。作为后续工作，在表现出条件性 IL-1β 表达的大脑区域中，我们将通过检查位点特异性重组 IL-1β 输注的效果，探讨在没有海洛因条件作用的情况下，IL-1β 是否足以诱导免疫抑制。具体目标 II 将检验 IL-1beta 的假设 特定脑区的基因表达对于海洛因条件免疫调节的表达是必需的。为了证明 IL-1β 表达对于海洛因条件免疫调节是必需的，我们将检查抑制特定脑区域的 IL-1β 表达对海洛因条件免疫调节的影响。使用小干扰 RNA (siRNA) 选择性抑制 DH、BLA、NAC 或 VTA 中的 IL-1beta 基因表达，或者使用同一脑区域中的 IL-1 受体拮抗剂阻断 IL-1 受体。具体目标 III 将检验以下假设：DH 中的 IL-1beta 基因表达对于海洛因配对环境的条件激励作用（促进药物寻求）是必需的。我们将使用条件位置偏好 (CPP) 范式来测试 IL-1β 表达对于药物配对情境刺激的激励作用是否是必要的，因为它与海洛因条件免疫抑制程序相似。我们还将使用情境恢复范式评估 IL-1β 表达对于药物情境诱导的海洛因寻求行为的恢复是否是必要的，该范式是一种具有特殊面孔和预测有效性的药物复发模型。总体而言，该项目采用创新方法揭示药物条件刺激影响免疫功能和药物复发的新神经免疫学机制，从而从根本上增强我们对阿片类药物使用对健康后果的理解，并为开发新型神经免疫疗法以恢复免疫功能和预防药物复发提供信息。