CHOLINERGIC PHARMACOLOGY OF BASAL FOREBRAIN NEURONS

这项工作的长期目标是开发一种药理 认知功能障碍的治疗方案 胆碱能神经元与衰老和阿尔茨海默病有关。 具体地说，这个项目将研究胆碱能 胆碱能神经元投射的调控机制 大脑皮层和海马体。多种胆碱能 具有不同地区分布的受体已经被 在中枢神经系统中被识别。据推测， 胞体区域胆碱能受体的兴奋作用 基底前脑胆碱能神经元对此有抑制作用 神经元。此外，这些受体可能显著不同。 突触后胆碱能受体使胆碱能 胆碱能有效增强神经传递 阻断突触前受体但不阻断突触后受体的拮抗剂 感受器。参与这一机制的胆碱能受体 将在一种动物模型中被表征，该动物模型允许研究 部分激动剂和拮抗剂对血管紧张素转换酶活性的影响 胆碱能神经元及其行为在一个完整、全功能的 动物。核内注射胆碱能药物的作用 经长期植入导向器引导基底肌或内侧间隔 将研究插管对额叶胆碱能活动的影响 大脑皮层、顶叶皮质和海马区与意识中的记忆 老鼠。中枢胆碱能活动将通过以下方式评估 乙酰胆碱(ACh)周转率的质量量化 一种衡量相对并入的碎片化技术 从磷胆碱到胆碱和乙酰胆碱。 八臂径向迷宫将用于测试记忆并获得一个 ACh周转的功能相关性。基底膜的作用 前脑(基底核或内侧隔)注射 卡巴胆碱、尼古丁和氧化曲莫林-M将在ACh上进行研究 周转和短期的，或工作的，记忆。此外， 根据激动剂研究的结果， 下列部分或全部拮抗剂可阻断 卡巴胆碱，将被研究：甲氨基甲胺，阿托品，哌仑西平， AF-DX 116和六氢硅烷-地芬尼多。

The long-term goal of this work is to develop a pharmacological treatment regimen for the cognitive dysfunctions involving cholinergic neurons associated with aging and Alzheimer's disease. Specifically, this project will investigate the cholinergic mechanisms involved in regulating cholinergic neurons projecting to the cortex and hippocampus. Multiple types of cholinergic receptors with differing regional distributions have been identified in the central nervous system. It is postulated that stimulation of cholinergic receptors in the region of cell bodies of basal forebrain cholinergic neurons is inhibitory to these neurons. Furthermore, these receptors may differ significantly from postsynaptic cholinergic receptors so that cholinergic neurotransmission can be effectively enhanced by cholinergic antagonists which block presynaptic receptors but not postsynaptic receptors. The cholinergic receptors involved in this mechanism will be characterized in an animal model which allows the study of the effect of selected agonists and antagonists on the activity of cholinergic neurons and on behavior in an intact, fully functional animal. The effect of cholinergic drugs injected into the nucleus basalis or the medial septum through chronically-implanted guide cannulas will be studied on cholinergic activity in the frontal cortex, parietal cortex and hippocampus and on memory in conscious rats. Central cholinergic activity will be assessed by quantitating acetylcholine (ACh) turnover by a mass fragmentographic technique that measures the relative incorporation of deuterium label from phosphorylcholine into choline and ACh. The 8-arm radial maze will be used to test memory and obtain a functional correlate of ACh turnover. The effect of intra-basal forebrain (nucleus basalis or medial septum) injection of carbachol, nicotine, and oxotremorine-M will be studied on ACh turnover and short-term, or working, memory. Furthermore, depending upon the results of the agonist studies, the ability of some or all of the following antagonists to block the action of carbachol, will be studied: mecamylamine, atropine, pirenzepine, AF-DX 116 and hexahydrosila-difenidol.