NEUROLOGICAL TARGETS OF ANTIDEPRESSANTS IN C ELEGANS

线虫抗抑郁药的神经学靶标

• 批准号: 2697306
• 负责人: JAMES H THOMAS
• 金额: $ 11.69万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2697306
• 关键词: Caenorhabditis elegans; drug resistance; fluoxetine; gene mutation; molecular psychobiology; neurotransmitter transport; pharmacokinetics; protein localization; psychopharmacology

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.

描述（改编自申请人的摘要）：SSRI 抗抑郁药， 包括氟西汀（百忧解），是最常开的药物 治疗抑郁症。 氟西汀的体内靶标 是其抗抑郁作用的原因，但其副作用却不是 建立良好。 在人类或 在哺乳动物抑郁症模型中这是不可能的。 我们正在使用 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具有三种作用： 对秀丽隐杆线虫有明显的影响。 这些影响之一可能是由于 阻断血清素再摄取，正如哺乳动物中一个已知目标所预期的那样。 另外两种作用似乎与血清素无关。 我们已经隔离了 七个基因的突变赋予其中一种抗性 氟西汀（Nrf 突变体）的非血清素作用。 我们有分子 克隆了其中一个基因，称为 nrf-6。 nrf-6 对定义成员进行编码 多次跨膜蛋白家族的成员。 我们建议调查 nrf-6 通过完成初始分子分析并确定其 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 我们已经鉴定出氟西汀抗性基因并执行类似的操作 分析与 nrf-6 相同。 我们建议继续进行诱变筛选 识别介导鼻子收缩和其他氟西汀的其他基因 回应。 最后，我们建议在哺乳动物中鉴定新的成员 nrf-6家族作为确定是否 线虫-氟西汀相互作用可能与人类有直接关系。