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）对免疫功能有毁灭性的影响，并导致上瘾的行为。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鲁棒的，但是这些作用的神经机制知之甚少。我们为理解条件免疫调节和动机的神经回路做出了重大贡献。在这些发现的基础上，该R01提案将检验总体假设，即海洛因调节和寻求药物的动机取决于细胞因子介导的中枢神经系统信号，由细胞因子Interleukin-1Beta（IL-1Beta）介导。具体目的我将检验以下假设：暴露于海洛因条件的刺激与中枢神经系统内不同大脑区域和细胞类型中的IL-1BETA表达有关。我们将评估在背侧海马（DH），基底外侧杏仁核（BLA），副壳壳（NACS）和腹侧围壳区域（VTA），暴露于海洛因标记的上下文或旨在确定适当的条件性的控制后，均为对条件的情况下的变化后，评估IL-1BETA表达的变化。我们将确定这些效果涉及的特定细胞类型。随后，在表现出条件IL-1BETA表达的大脑区域中，我们将探索IL-1BETA是否足以在没有海洛因调节的情况下诱导免疫抑制，并检查现场特异性重组IL-1Beta输注的作用。具体目标II将检验IL-1Beta的假设 在特定的大脑区域中，基因表达对于海洛因条件的免疫调节表达是必要的。为了证明IL-1BETA表达对于海洛因调节的免疫调节是必不可少的，我们将研究抑制特定脑区域中IL-1BETA表达对海洛因调节免疫调节的影响。使用小型干扰RNA（siRNA）或IL-1受体将使用同一大脑区域的IL-1受体拮抗剂阻断DH，BLA，NACS或VTA中的IL-1BETA基因表达。具体目的III将是检验以下假设：DH中IL-1Beta基因的表达对于促进促进药物寻求药物的海洛因生态环境的条件动机作用是必要的。我们将测试IL-1BETA表达对于使用条件的位置偏好（CPP）范式的药物配对刺激的动机作用是否是必要的，鉴于其与海洛因条件条件的免疫抑制程序相似。我们还将评估使用上下文恢复原状范式对药物上下文诱导的寻求海洛因寻求行为的恢复是否需要的IL-1Beta表达是必要的，这是一种具有出色的面部和预测有效性的药物复发模型。总体而言，该项目采用了一种创新的方法来揭示新型的神经免疫学机制，通过这些方法，药物条件的刺激会影响免疫功能和药物复发，从而从根本上增强了我们对阿片类药物使用的健康后果的理解，并告知新型神经免疫性疗法的发展，以恢复免疫功能和预防药物复发。