Role of IL-1 in Heroin's Immune and Motivational Effects

描述(申请人提供)：滥用毒品，如海洛因，对免疫功能有毁灭性的影响，并导致上瘾行为。值得注意的是，海洛因的这些作用受到环境刺激的制约。由此产生的条件性免疫调节和激励效应是强大的，但这些效应的神经机制尚不清楚。我们在理解条件性免疫调节和动机背后的神经回路方面做出了重大贡献。在这些发现的基础上，这项R01提案将测试最重要的假设，即海洛因条件免疫调节和寻求药物的动机依赖于由细胞因子白介素1β(IL-1β)介导的改变的中枢神经系统信号。具体目的我将测试这一假设，即暴露在海洛因条件刺激下与中枢神经系统内不同脑区和细胞类型的IL-1β表达有关。我们将评估IL-1β在暴露于海洛因条件化环境或对照操作后，在背侧海马区(DH)、杏仁基底外侧核(BLA)、伏隔核外壳(NAC)和腹侧被盖区(VTA)的表达随时间的变化，以确定这些变化是否由条件反射本身造成。我们将确定参与这些效应的特定细胞类型。作为后续，我们将通过检测特定部位重组IL-1β输注的效果，在显示有条件的IL-1β表达的脑区，探索IL-1β是否足以在没有海洛因条件下诱导免疫抑制。特殊目的II将检验IL-1β的假设 海洛因条件性免疫调节的表达需要特定脑区的基因表达。为了证明IL-1β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-1β表达对海洛因条件性免疫调节的影响。利用小干扰RNA(SiRNA)选择性地抑制白介素1β基因在脑内的表达，或在相同脑区使用白介素1受体拮抗剂阻断白介素1受体。具体目标三将是测试这一假设，即在DH中IL-1β基因的表达对于海洛因配对环境的条件性激励作用是必要的，从而促进药物寻找。我们将使用条件性位置偏好(CPP)范式来测试IL-1β的表达是否对于药物配对的上下文刺激的动机效应是必要的，因为它类似于海洛因条件免疫抑制过程。我们还将使用情境恢复范式来评估IL-1β的表达是否对于药物情境诱导的海洛因寻找行为的恢复是必要的，情境回复范式是一种具有特殊外观和预测有效性的药物复发模型。总体而言，本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的神经免疫学机制，从而从根本上提高我们对阿片类药物使用的健康后果的了解，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提供信息。

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.