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

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制约的。由此产生的条件免疫调节和动机效应是强大的，但这些影响的神经机制尚不清楚。我们在理解条件免疫调节和动机背后的神经回路方面做出了重大贡献。基于这些发现，本R01提案将验证海洛因条件下的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改变的总体假设。我将测试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的il -1 β表达相关的假设。我们将评估暴露于海洛因条件下或经过控制操作后，背侧海马（DH）、基底外侧杏仁核（BLA）、伏隔核壳（NACs）和腹侧被盖区（VTA）中il -1 β表达随时间的变化，以确定这些变化是否由条件本身引起。我们将确定与这些效应有关的特定细胞类型。作为后续研究，在表现出条件il -1 β表达的脑区，我们将通过检查部位特异性重组il -1 β输注的效果，探索il -1 β是否足以在没有海洛因条件作用的情况下诱导免疫抑制。特异性目标II将测试il -1 β的假设

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.