The Neurokinin-1 Receptor as a Mediator of Alcoholism and Depression Comorbidity

项目总结/摘要 酒精中毒与其他精神疾病有显著的共病性。之一 这些共病疾病中最突出的是重度抑郁症，酗酒者在 与非酗酒者相比，患重度抑郁症的风险大约高出四倍。 在这个提议中，我们将研究通过诱导共- 使用临床前啮齿类动物， 模型具体来说，我们将使用暴露于慢性社会失败压力来诱导这些 行为表型我们将检验神经激肽-1受体（NK 1 R） 介导社交失败压力暴露对随后酒精摄入的影响， 类似抑郁的行为我们之前已经证明这种受体会影响压力- 诱导啮齿动物的酒精寻求，因此，这种受体是影响的理想靶点。 社交压力诱导的酒精摄入。关于失败压力，我们 发现NK 1 R在对这种压力敏感的动物中上调。然而，在这方面， 失败应激模型的一个缺点是，由于性别原因， 领土侵略的差异。这对于本文所研究的概念来说是一个有意义的问题 因为临床抑郁症在女性中比在男性中更常见。因此，我们将使用 不同的应激源，细菌细胞壁成分脂多糖的免疫刺激 (LPS)，研究这些行为在两性。已知LPS会增加酒精摄入量， 抑郁样行为在雄性和雌性小鼠，我们的初步数据表明， LPS的某些作用依赖于NK 1 R。这些因素共同造就了LPS 注射相关模型，以检查男女酗酒和抑郁症的共病。 NK 1 R在LPS作用中的作用表明，类似的神经回路可能调节LPS的作用。 对失败压力和LPS诱导的行为改变的反应。的结果予以 研究将大大有助于我们了解影响共病的因素， 酒精中毒和抑郁症，并将确定新的候选目标的药物 发展

Project Summary/Abstract There is a significant comorbidity of alcoholism with other psychiatric conditions. One of the most prominent of these comorbid disorders is major depression, where alcoholics are at approximately four-fold greater risk of experiencing major depression relative to non-alcoholics. In this proposal we will examine the mechanisms that mediate this comorbidity by inducing co- expressed depressive-like behavior and escalated alcohol consumption using preclinical rodent models. Specifically, we will use exposure to chronic social defeat stress to induce these behavioral phenotypes. We will examine the hypothesis that the neurokinin-1 receptor (NK1R) mediates the influence of social defeat stress exposure on subsequent alcohol intake and depressive-like behavior. We have previously shown that this receptor influences stress- induced alcohol seeking in rodents, and as such, this receptor is an ideal target to influence social stress-induced alcohol intake in this mouse model. In specific regard to defeat stress, we have found that the NK1R is upregulated in animals that are sensitive to this stressor. However, one drawback of the defeat stress model is that it can only be used in male mice due to sex differences in territorial aggression. This is a significant issue for the concepts studied here because clinical depression is far more common in females than in males. Thus, we will use a different stressor, immune stimulation by the bacterial cell wall component lipopolysaccharide (LPS), to study these behaviors in both sexes. LPS is known to increase alcohol intake and depressive-like behavior in both male and female mice, and our preliminary data indicates that some effects of LPS are dependent upon the NK1R. Together, these aspects make LPS injection a relevant model for examining alcoholism and depression comorbidity in both sexes. The role of the NK1R in LPS effects suggests that a similar neurocircuitry may regulates the response to both defeat stress and LPS-induced behavioral alterations. The results of these studies will significantly contribute to our understanding of the factors that influence comorbid alcoholism and depression, and will identify novel candidate targets for medications development.