Neural Mechanisms of Heroin-induced Conditioned Immunomodulation

在长期海洛因使用者中，细菌、病毒和真菌机会性感染的发病率很高。我们的实验室是第一个证明，值得注意的是，与海洛因管理配对的环境刺激获得海洛因样的免疫调节特性作为联想学习过程的结果。因此，阿片类药物的有害健康后果可以适应于预测给药的环境刺激。拟议的研究是第一个特点的作用，多巴胺在丘脑核和杏仁核的条件免疫调节作用的海洛因。这些研究将评估多巴胺受体拮抗剂的核内给药和杏仁核内给药对促炎性免疫反应表达中海洛因条件性改变的影响。脂多糖（LPS）将用于激发免疫系统。LPS是革兰氏阴性菌的免疫原性组分，其诱导强烈的促炎性免疫应答，并且已充分确定海洛因配对刺激减弱这些免疫应答的表达。具体目标我测试的假设，即刺激多巴胺受体在丘脑核是必要的表达条件阿片类药物诱导的减少在体内促炎细胞因子和一氧化氮的生产。拟议的调查提供了一个全面的评估，在海洛因条件的免疫调节的表达中的作用，核多巴胺受体。具体目标II测试的假设，在杏仁核中的多巴胺受体刺激是必要的，以产生条件阿片类药物诱导的减少在体内促炎细胞因子和一氧化氮的表达。拟议的调查确定杏仁多巴胺受体的作用，在海洛因条件的免疫调节使用选择性多巴胺受体拮抗剂的表达。具体目标III测试的假设，杏仁核和脑桥核的顺序信息处理是必要的海洛因诱导的条件性免疫调节。拟议的实验将评估是否杏仁核和脑桥核之间的通信是必要的海洛因诱导的条件免疫调节的表达。这些实验尤其重要，因为它们是第一个研究介导这一重要功能的大脑区域之间的系统级相互作用的实验。总的来说，这些研究为条件阿片类药物/免疫相互作用的神经解剖学底物和多巴胺受体机制提供了新的见解，并在我们对阿片类药物使用的健康后果的理解方面取得了重要进展。

There is high incidence of bacterial, viral, and fungal opportunistic infections among long-term heroin users. Our laboratory was the first to demonstrate that, remarkably, environmental stimuli paired with heroin administration acquire heroin-like immunomodulatory properties as a result of associative learning processes. Thus, the detrimental health consequences of opiates can be conditioned to environmental stimuli predictive of drug administration. The proposed studies are the first to characterize the role of dopamine in the nucleus accumbens and amygdala in the conditioned immunomodulatory effects of heroin. The studies will assess the effects of intra-nucleus accumbens and intra-amygdala administration of dopamine receptor antagonists on heroin-conditioned alterations in the expression of proinflammatory immune responses. Lipopolysaccharide (LPS) will be used to challenge the immune system. LPS is an immunogenic component of Gram-negative bacteria that induces robust proinflammatory immune responses, and it is well established that heroin-paired stimuli attenuate the expression of these immune responses. Specific Aim I tests the hypothesis that stimulation of dopamine receptors in the nucleus accumbens is necessary for the expression of conditioned opioid-induced reductions in the production of in vivo proinflammatory cytokines and nitric oxide. The proposed investigations provide a comprehensive assessment of the role of nucleus accumbens dopamine receptors in the expression of heroin-conditioned immunomodulation. Specific Aim II tests the hypothesis that dopamine receptor stimulation in the amygdala is necessary to produce the expression of conditioned opioid-induced reductions in the in vivo proinflammatory cytokines and nitric oxide. The proposed investigations determine the role of amygdalar dopamine receptors in the expression of heroin-conditioned immunomodulation using selective dopaminergic receptor antagonists. Specific Aim III tests the hypothesis that sequential information processing by the amygdala and nucleus accumbens is necessary for heroin-induced conditioned immunomodulation. The proposed experiments will evaluate whether communication between the amygdala and nucleus accumbens is necessary for expression of heroin-induced conditioned immunomodulation. These experiments are especially important for they are the first to examine systems-level interaction between brain regions mediating this important function. Collectively, these studies provide new insights into the neuroanatomical substrates and dopamine receptor mechanisms of conditioned opioid/immune interactions, and make important advancements in our understanding of the health consequences of opioid use.