CHOLINERGIC PHARMACOLOGY OF BASAL FOREBRAIN NEURONS

这项工作的长期目标是开发一种药理学 认知功能障碍的治疗方案， 与衰老和阿尔茨海默病相关的胆碱能神经元。 具体来说，该项目将研究胆碱能 参与调节胆碱能神经元投射的机制 大脑皮层和海马体 多种胆碱能 具有不同区域分布的受体， 在中枢神经系统中被发现。 据推测 刺激细胞体区域中的胆碱能受体 基底前脑胆碱能神经元对这些抑制作用 神经元 此外，这些受体可能显著不同， 从突触后胆碱能受体， 胆碱能神经递质能有效地增强神经传递， 阻断突触前受体但不阻断突触后受体的拮抗剂 受体。 参与这一机制的胆碱能受体 将在动物模型中表征，该模型允许研究 所选激动剂和拮抗剂对以下活性的影响： 胆碱能神经元和行为在一个完整的，功能齐全的 动物 核内注射胆碱能药物的作用 通过长期植入的导向器， 将研究插管对额叶胆碱能活性的影响 大脑皮层、顶叶皮层和海马体以及意识状态下的记忆 大鼠 将通过以下方法评估中枢胆碱能活性： 乙酰胆碱（ACh）周转定量质量 碎片图技术，测量相对结合 从磷酰胆碱到胆碱和乙酰胆碱的氘标记。 八臂径向迷宫将用于测试记忆并获得一个 ACh周转的功能相关物。 基底层内 前脑（基底核或内侧隔）注射 氨甲酰胆碱、尼古丁和氧化震颤素-M将在ACh 周转率和短期或工作记忆。 此外，委员会认为， 根据激动剂研究的结果， 一些或所有下列拮抗剂，以阻断 卡巴胆碱，将被研究：美加明，阿托品，哌仑西平， AF-DX 116和六氢硅-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.