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: 9230828
• 负责人: Rita A Fuchs Lokensgard
• 金额: $ 37.54万
• 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/9230828
• 关键词: Addictive Behavior; Affect; Amygdaloid structure; Behavior; Binding; Biological Response Modifiers; Brain; Brain region; Conditioned Reflex; Data; Development; Dorsal; Drug Addiction; Drug Modelings; 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 Receptors; Interleukin-1 beta; Investigation; Label; Laboratories; Lead; Measurement; Mediating; Motivation; Neuraxis; Neurons; Nucleus Accumbens; Opiates; Peripheral; Pharmaceutical Preparations; Population; Procedures; Publishing; Quantitative Reverse Transcriptase PCR; RNA Interference; Rattus; Recombinant Interleukin-1; Recombinant Interleukins; Research; Role; Signal Transduction; Signaling Molecule; Site; Small Interfering RNA; Stimulus; Testing; Time; Ventral Tegmental Area; anakinra; base; brain cell; cell type; conditioning; cytokine; design; drug of abuse; drug relapse; drug seeking behavior; experimental study; follow-up; immune function; immunoregulation; innovation; interdisciplinary approach; mRNA Expression; mind control; neural circuit; neuromechanism; novel; novel strategies; opioid use; preference; prevent; protein expression; public health relevance; 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，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。由此产生的条件免疫调节和激励作用是强大的，但这些影响的神经机制知之甚少。我们对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，R 01提案将测试总体假设，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-1 β（IL-1 β）介导的中枢神经系统信号传导的改变。具体目的我将测试的假设，暴露于海洛因条件刺激与IL-1 β在不同的大脑区域和CNS内的细胞类型的表达。我们将评估IL-1 β表达随时间的变化，背海马（DH），基底外侧杏仁核（BLA），核壳（NAC），腹侧被盖区（VTA），暴露于海洛因条件的情况下，或控制操作后，旨在确定这些变化是否是由于条件本身。我们将确定参与这些效应的特定细胞类型。作为后续，在表现出条件性IL-1 β表达的脑区，我们将通过检查位点特异性重组IL-1 β输注的影响，探索在没有海洛因条件作用的情况下IL-1 β是否足以诱导免疫抑制。Specific Aim II将检验IL-1 β 基因表达在特定脑区域中对于海洛因调节的免疫调节的表达是必需的。为了证明IL-1 β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IL-1 β在特定脑区的表达对海洛因条件性免疫调节的影响。使用小干扰RNA（siRNA）选择性抑制DH、BLA、NAC或VTA中的IL-1 β基因表达，或使用IL-1受体拮抗剂阻断相同脑区中的IL-1受体。具体目标III将测试的假设，即IL-1 β基因表达的DH是必要的条件激励效应的海洛因配对的背景下，促进药物寻求。我们将测试是否IL-1 β的表达是必要的药物配对的背景刺激的动机效应，使用条件性位置偏好（CPP）的范例，鉴于其相似的海洛因条件免疫抑制程序。我们还将评估IL-1 β表达是否是必要的药物上下文诱导的海洛因寻求行为的恢复使用上下文的恢复范例，一个模型的药物复发异常的脸和预测效度。总的来说，该项目采用创新的方法来揭示药物条件刺激影响免疫功能和药物复发的新型神经免疫学机制，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，并为开发新型神经免疫学疗法提供信息，以恢复免疫功能和预防药物复发。