ELECTROPHYSIOLOGICAL TESTING OF DRUG COMBINATIONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 考利实验室和其他实验室最近的研究表明，下丘脑中的神经元回路是许多能量状态信号的共同途径。这项工作的各个方面也证明了这个下丘脑回路是芬氟拉明引起体重减轻的靶点，这一途径对于芬氟拉明诱导的体重减轻是必要的。尽管芬氟拉明不再被用作体重控制剂，但其他更安全的药物的作用方式与芬氟拉明相似。临床数据和对神经元回路的详细研究表明，几种药物组合可能会协同作用，激活控制体重的下丘脑回路。特别是，假设阻断这些回路的自动抑制将使它们保持活跃，并对体重控制药物做出反应。这项提案中概述的工作将评估三种不同类别的药物组合对下丘脑神经元活动的影响，以及对小鼠和大鼠摄食量和体重的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent work in the Cowley lab, and other laboratories, has demonstrated that a neuronal circuit within the hypothalamus functions as a common pathway for many signals of energy state. Aspects of this work also demonstrated that this hypothalamic circuitry was the target through which fenfluramine acted to cause weight loss, and that this pathway is necessary for fenfluramine induced weight loss. Although fenfluramine is no longer used as a weight control agent, other safer drugs act in a similar manner to fenfluramine. Clinical data, and detailed study of the neuronal circuitry, has suggested several drug combinations that may act synergistically to activate the hypothalamic circuits that control body weight. In particular, it is hypothesized that blocking auto-inhibition of these circuits will allow them to remain active and responsive to weight control drugs. The work outlined in this proposal will assess the effects of three different classes of drug combination on the activity of hypothalamic neurons, and on food intake and body weight in mice and rats.