NEUROLOGICAL TARGETS OF ANTIDEPRESSANTS IN C ELEGANS

描述（改编自申请人的摘要）：SSRI抗抑郁药， 包括氟西汀（百忧解），是最常用的药物， 治疗抑郁症。 氟西汀的体内靶点， 负责其抗抑郁作用，其副作用不是 很好地建立了。 在人体内系统地建立这种靶点， 在哺乳动物抑郁症模型中是不可能的。 我们使用 线虫秀丽隐杆线虫，以确定氟西汀的作用机制。 在初步研究中，我们已经确定氟西汀有三个 在C.优雅 这些影响之一可能是由于 阻断5-羟色胺再摄取，正如哺乳动物中一个已知靶点所预期的那样。 另外两种效应似乎与血清素无关。 我们已经分离出 七个基因的突变赋予了对其中一种 氟西汀（Nrf突变体）的非神经递质效应。 我们在分子水平上 克隆了其中一个基因，叫做nrf-6。 NRF-6编码限定元件 一个多通道跨膜蛋白家族的成员。 我们建议调查 通过完成这一初步的分子分析，并通过确定其 表达模式、亚细胞定位和功能位点， 赋予氟西汀敏感性。 我们建议克隆另外两个 氟西汀耐药基因，我们已经确定，并进行类似的 对nrf-6的分析。 我们建议继续进行诱变筛选， 确定其他基因介导的鼻子收缩和其他氟西汀 应答 最后，我们建议在哺乳动物中识别新的 NRF-6系列作为确定是否 线虫-氟西汀相互作用可能与人类直接相关。

DESCRIPTION (Adapted from applicant's abstract): The SSRI antidepressants, including fluoxetine (Prozac), are the drugs most commonly prescribed for treatment of depressive disorders. The in vivo targets of fluoxetine that are responsible for its antidepressive effects and its side effects are not well established. Systematically establishing such targets in the human or in mammalian models of depression is not possible. We are using the nematode Caenorhabditis elegans to identify mechanisms of fluoxetine action. In preliminary studies we have established that fluoxetine has three distinct effects in C. elegans. One of these effects is probably due to blocking serotonin reuptake, as expected from one known target in mammals. The other two effects appear not to involve serotonin. We have isolated mutations in seven genes that confer resistance to one of the non-serotonergic effects of fluoxetine (Nrf mutants). We have molecularly cloned one of these genes, called nrf-6. nrf-6 encodes the defining member of a family of multi-pass transmembrane proteins. We propose to investigate nrf-6 by completing this initial molecular analysis and by determining its expression pattern, subcellular localization, and site of function in conferring fluoxetine sensitivity. We propose to clone two additional fluoxetine resistance genes that we have identified and to perform similar analyses as for nrf-6. We propose to continue mutagenesis screens to identify other genes that mediate the nose contraction and other fluoxetine responses. Finally, we propose to identify in mammals members of the new nrf-6 family as a first step toward determining whether the nematode-fluoxetine interaction might have direct relevance to humans.