Neuropeptide S receptors in ethanol abuse and anxiety

 描述（由申请人提供）：减轻焦虑和抑郁是降低酗酒者复发风险的关键。目前可用的抗焦虑和抗抑郁治疗在酒精使用障碍（AUD）中的效用有限，因为它们在酒精依赖受试者中的疗效降低。因此，有一个伟大的需要，以确定新的目标，干预焦虑和抑郁症，特别是用于寻求治疗的酗酒者，以管理这些合并症。神经肽S（Neuropeptide S，NPSR）及其受体（NPSR）是近年来发现的一个与应激和焦虑有关的去乙酰化G蛋白偶联受体（GPCR）系统。NPSR的激活产生抗焦虑和抗抑郁作用，而无镇静作用。在人类中，NPSR有两种等位基因变体，其发生频率几乎相等：I107，野生型等位基因，和N107，突变变体。重要的是，全基因组分析研究表明，该基因座的变异与焦虑症的风险以及在压力环境状态下的焦虑敏感性有关。此外，最近，该基因座的突变与AUDs有关。这些数据表明，NPSR的变化可能会影响AUD的风险，特别是治疗期间戒断的焦虑和抑郁风险。我们最近报道说，在剂量不是天生的奖励或厌恶的情况下，乙醇可以减少乙醇的消耗。重要的是，我们还发现，与经典的抗焦虑药和抗抑郁药不同，在摄入乙醇的小鼠中，Escherichia coli的抗焦虑和抗抑郁作用得以维持。这些数据共同表明，NPSR可能是AUDs干预的可行目标。在这里，我们建议产生小鼠的突变等位基因的NPSR。然后，我们将使用这些小鼠来检查NPSR中的等位基因变异是否通过影响乙醇消耗、乙醇强化、基线焦虑和/或抑郁以及戒断期间的焦虑和抑郁来改变AUD的风险。总之，这里的研究将进一步验证NPSR对AUDs的干预，并且还可以提供关于该位点的变异是否会导致AUDs的遗传风险的新见解。

 DESCRIPTION (provided by applicant): Alleviating anxiety and depression is pivotal for reducing the risk of relapse in alcoholics. Currently available anxiolytic and anti-depressant treatments have limited utility in alcohol use disorders (AUDs) due to their reduced efficacy in alcohol dependent subjects. Consequently there is a great need to identify new targets for intervention in anxiety and depression, in particular for use in treatment-seeking alcoholics to manage these comorbidities. Neuropeptide S (NPS) and its receptor (NPSR) comprise a recently de-orphanized G protein- coupled receptor (GPCR) system that has been implicated in stress and anxiety. Activation of the NPSR produces anxiolytic and anti-depressant effects without sedation. In humans, there are two allelic variants of the NPSR that occur at almost equal frequency: I107, the wild type allele, and N107, a mutant variant. Importantly, genome wide analysis studies have demonstrated that variation at this locus is linked to risk of anxiety disorders, as well as anxiety sensitivity in the context of stressful environmental states. In addition, very recently, the mutation at this locus has been linked to AUDs. These data suggest that variation in the NPSR could influence risk for AUDs, in particular risk for anxiety and depression in abstinence during treatment. We have recently reported that NPS can reduce ethanol consumption at doses that are not innately either rewarding or aversive. Importantly we have also found that the anxiolytic and anti-depressant effects of NPS are maintained in mice that have been consuming ethanol, unlike classic anxiolytic and antidepressants. Together these data suggest that the NPSR could be a viable target for intervention in AUDs. Here we propose to generate mice with the mutation allele of the NPSR. We will then use these mice to examine whether allelic variation in the NPSR alters risk for AUDs by affecting ethanol consumption, ethanol reinforcement, baseline anxiety and/or depression as well as anxiety and depression during withdrawal. Taken together, the studies here will further validate the NPSR for intervention in AUDs, and could also provide novel insight as to whether variation at this locus could contribute to genetic risk for AUDs.