ESTROGEN EFFECTS ON CHOLINERGIC FUNCTION IN OLDER WOMEN

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 该项目的主要目标是利用临床和认知研究来确定雌激素和相关化合物如何影响人类大脑胆碱能系统的功能。我们将在整个提案中使用的基本模型是利用胆碱能拮抗剂药物测试性腺类固醇对神经化学“损伤”模型的影响。 这种方法通过暂时阻断突触前和突触后毒蕈碱和烟碱胆碱能受体来模拟年龄或疾病相关的神经受体和/或神经元损失的影响。 该模型可靠地产生轻度和可量化但快速可逆的认知障碍，并已被证明在理解胆碱能系统的作用及其对人类认知功能的丧失方面很有价值。 我们已经成功地利用该模型建立了衰老和神经退行性疾病中毒蕈碱和烟碱胆碱能受体丢失的影响。 我们现在已经扩展了这个模型，以研究雌激素替代对正常衰老中胆碱能功能和认知能力的影响。 假设： 1.与急性给予E2（例如通过药理学机制）相比，长期给予E2超过3个月将产生显著更大的胆碱能功能增强（可能通过营养机制）。 这将通过减弱胆碱能拮抗剂东莨菪碱（毒蕈碱）和美加明（烟碱）对注意力、运动速度、语言学习和记忆的性能损害作用来证明。 2. E2单独给药3个月将减弱毒蕈碱和烟碱胆碱能拮抗剂药物的负面认知和性能影响，其程度显著大于E2 + Progestrin（PRO）的组合。这些影响将表现在视觉空间学习和记忆、运动速度和言语工作记忆的任务上。 3.雌激素拮抗剂他莫昔芬将增强胆碱能拮抗剂对视觉空间学习和记忆、运动速度和言语工作记忆任务的认知损害作用，继发于对中枢神经系统中胆碱能系统完整性的负面影响。

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. The primary goal of this project is to use clinical and cognitive investigations to establish how estrogen and related compounds influence the functioning of the cholinergic systems of the human brain. The basic model that we will use throughout this proposal is to test the effects of gonadal steroids on a neurochemical "lesion" model utilizing cholinergic antagonist drugs. This approach simulates the effects of age- or disease-related neuroreceptor and/or neuronal loss by temporarily blocking pre- and postsynaptic muscarinic and nicotinic cholinergic receptors. This model reliably produces mild and quantifiable but rapidly reversible cognitive impairment and has proved valuable in understanding the role of the cholinergic system and its loss on human cognitive functioning. We have utilized this model successfully to establish the effects of the loss of muscarinic and nicotinic cholinergic receptors in aging and neurodegenerative disorders. We have now extended this model to examine the effects of estrogen replacement on cholinergic function and cognitive performance in normal aging. Hypotheses: 1. Chronic administration of E2 over three months will produce significantly greater enhancement of cholinergic function (potentially through a trophic mechanism) than acutely administered E2 (e.g. through a pharmacologic mechanism). This will be manifested by blunting the performance-impairing effects of the cholinergic antagonists scopolamine (muscarinic) and mecamylamine (nicotinic) on attention, motor speed, verbal learning and memory. 2. E2 administered alone for 3 months will blunt the negative cognitive and performance effects of muscarinic and nicotinic cholinergic antagonist drugs, to a significantly greater degree than the combination of E2 plus Progesterone (PRO). These effects will be manifested on tasks of visuo-spatial learning and memory, motor speed, and verbal working memory. 3. The estrogen antagonist tamoxifen will enhance the cognition-impairing effects of cholinergic antagonists on tasks of visuo-spatial learning and memory, motor speed, and verbal working memory secondary to negative effects on cholinergic system integrity in the central nervous system.