Neuropeptide receptors, behavioral states and acute ethanol effects

项目摘要 本研究有两个部分重叠的目标：（1）全面定义G蛋白的阵列- 偶联神经肽受体，用于调节和介导体内乙醇的急性作用。（二） 研究特定行为状态对乙醇急性敏感性的影响。我们将描述 所有神经肽受体在C. elegans在基础运动行为和乙醇诱导行为中的作用 方面的影响.这种全面的评估将确定受体的积极和消极调节 控制运动的神经元回路和那些促进或负调节乙醇的受体 行动我们将评估对乙醇的初始敏感性水平和与时间相关的 对药物的急性功能性耐受。此外，对于那些调节乙醇反应的受体， 我们将对与神经肽酶nep-2的任何相互作用进行分类，nep-2是哺乳动物的直链酶。 脑啡肽酶蛋白。哺乳动物脑啡肽酶蛋白参与多种重要的神经递质水平的调节。 信号肽，包括脑啡肽，速激肽，P物质等。nep-2基因的突变 产生耐乙醇的行为表型。我们假设NEP-2的肽靶， 可能在NEP-2突变体背景下升高，通过增加乙醇的浓度来抵消乙醇的急性作用。 通过神经肽受体传递信号。拟议中的实验将识别这种受体，并测试其生物学特性。 这一假说认为，受体在一个确定的神经回路中起作用，控制行为状态的决定。我们 初步数据已经确定了几种影响乙醇反应和行为状态的突变体 影响探索行为的决策。调节该决定的电路是明确定义的，包括 神经肽和血清素的作用部位。我们将定义基因网络， 行为决定和乙醇反应，并测试控制回路中的特定神经元在 调节乙醇反应。人类的情绪（或情感）状态与 滥用药物的问题性使用引起了极大的关注。这项研究的成功结果 将更好地理解特定的行为状态，由已知的调节电路控制， 会影响对滥用药物的急性反应有一个显着的相关性之间的水平， 个人对酒精的最初反应及其发展为酒精使用障碍（AUD）的可能性。遗传 C.的任何人类直系同源物中的变异。这项研究中发现的线虫基因有可能改变 一个人对乙醇的反应水平，因此可能会影响这个人的易感性， 在以后的生活中开发AUD。

PROJECT SUMMARY There are two, partially overlapping goals of this research: (1) comprehensively define the array of G protein- coupled neuropeptide receptors that act to modulate and mediate acute actions of ethanol in vivo. (2) investigate the impact of specific behavioral states on acute sensitivity to ethanol. We will characterize the roles of all neuropeptide receptors in C. elegans in basal locomotion behaviors and ethanol-induced behavioral effects. This comprehensive assessment will identify receptors that positively and negatively regulate the neuronal circuit that controls locomotion and those receptors that act to promote or negatively regulate ethanol actions. We will assess both the level of initial sensitivity to ethanol and the time-dependent development of acute functional tolerance to the drug. In addition, for those receptors that act to modify responses to ethanol, we will classify any interactions with the neuropeptidase nep-2, which is orthologous to the mammalian neprilysin protein. The mammalian neprilysin protein is involved in the regulation of levels of multiple important signaling peptides, including enkephalins, tachykinin, substance P and others. A mutation in the nep-2 gene produces an ethanol-resistant behavioral phenotype. We hypothesize that a peptide target of NEP-2, which is likely to be elevated in a nep-2 mutant background, acts to counteract acute effects of ethanol via increased signaling through a neuropeptide receptor. The proposed experiments will identify that receptor and test the hypothesis that the receptor acts in a defined neuronal circuit that controls behavioral state decisions. Our preliminary data has identified several mutants that affect both ethanol responses and a behavioral state decision that affects exploratory behavior. The circuit that regulates that decision is well defined, and includes the sites of action of neuropeptides and serotonin. We will define networks of genes that act to regulate that behavioral decision and ethanol responses, and test specific neurons in the controlling circuit for their role in regulating ethanol responses. The relationship between an emotional (or affective) state in humans and the problematic use of drugs of abuse is of significant interest. The successful outcome of this proposed research will provide a better understanding of how specific behavioral states, controlled by a known regulatory circuit, can impact the acute responses to an abused drug. There is a significant correlation between the level of an individual’s initial response to alcohol and their likelihood to develop an alcohol use disorder (AUD). Genetic variation in any of the human orthologs of the C. elegans genes identified in this study has the potential to alter an individual’s level of response to ethanol, and therefore could impact that individual’s predisposition to develop an AUD later in life.