ELECTROPHYSIOLOGICAL TESTING OF DRUG COMBINATIONS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。考利实验室和其他实验室最近的工作表明，下丘脑内的神经元回路是许多能量状态信号的共同途径。这项工作的一些方面也表明，下丘脑回路是芬氟拉明作用导致体重减轻的目标，这一途径是芬氟拉明诱导体重减轻所必需的。虽然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与芬氟拉明相似。临床数据和对神经回路的详细研究表明，几种药物组合可能协同作用，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我抑制将使它们保持活跃并对体重控制药物作出反应。本提案中概述的工作将评估三种不同类型的药物组合对小鼠和大鼠下丘脑神经元活动、食物摄入和体重的影响。

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.