Neuropeptide S receptors in ethanol abuse and anxiety

 描述(申请人提供)：缓解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药物治疗对酒精使用障碍(AUD)的效用有限，因为它们对酒精依赖受试者的疗效降低。因此，迫切需要确定干预焦虑和抑郁的新目标，特别是用于寻求治疗的酗酒者来管理这些共病。神经肽S(NPS)及其受体(NPSR)是一个最近去孤儿的G蛋白偶联受体系统，与应激和焦虑有关。NPSR的激活在没有镇静的情况下产生了缓解焦虑和抗抑郁的效果。在人类中，有两个NPSR的等位基因变种出现的频率几乎相同：I107，野生型等位基因，和N107，突变变种。重要的是，全基因组分析研究已经证明，该基因座的变异与焦虑症的风险有关，以及在紧张的环境状态下的焦虑敏感性。此外，最近，这个基因的突变已经与AUDS联系在一起。这些数据表明，NPSR的变化可能会影响AUDS的风险，特别是在治疗期间戒酒时焦虑和抑郁的风险。我们最近报道，NPS可以减少乙醇消耗，剂量既不是天生的回报，也不是天生的厌恶。重要的是，我们还发现，与经典的抗焦虑和抗抑郁药物不同，NPS的抗焦虑和抗抑郁效果在服用乙醇的小鼠身上保持不变。总而言之，这些数据表明，NPSR可能是AUDS干预的可行靶点。在这里，我们建议用NPSR的突变等位基因来产生小鼠。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酒精消耗、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AUDS的风险。综上所述，这些研究将进一步验证NPSR对AUDS的干预作用，并可能为该基因变异是否会导致AUDS的遗传风险提供新的见解。

 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.