COGNITIVE LOSS WITH AGE--ROLE OF CORTICAL CATECHOLAMINES

随着年龄的增长认知能力丧失——皮质儿茶酚胺的作用

基本信息

批准号：
2442212
负责人：
AMY F.T. ARNSTEN
金额：
$ 22.6万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-12-01 至 1998-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2442212
关键词：
Macaca mulatta age difference aging alpha adrenergic agent alpha adrenergic receptor brain mapping dopamine dopamine agonists dopamine receptor frontal lobe /cortex learning stimulant memory norepinephrine psychopharmacology

项目摘要

DESCRIPTION (Adapted from applicant's abstract): The proposed experiments will determine whether improvements in delayed response performance produced by DA D1 or D2 agonists result from drug actions in the prefrontal cortex (PFC) enhancing the spatial working memory abilities of this cortex, or whether improvement results from nonspecific changes in performance variables. These issues are particularly important for D2 compounds, currently thought to have little influence on PFC function. Two methods will be used to address these questions: 1. D1 and D2 agonists (dihydrexidine and quinpirole, respectively) will be characterized in a thorough, dose-response manner in aged monkeys on the delayed response task, a task whose performance deteriorates with age, and on a battery of nonPFC tasks with different cognitive demands but similar motivational and motor requirements such as delayed response. These additional tasks will include delayed non-matching to sample, visual discrimination, route finding, and fine motor skills. Any effects of the agonists will be challenged with the antagonist of the same receptor subtype. The principal investigator will attempt to identify D1/D2 interactions by countering agonist effects with the antagonist at another subtype, and also by combining the D1 and D2 agonist to determine whether the combination will result in greater improvement than either agonist alone. 2. D1 or D2 compounds will be infused directly into the prefrontal cortex and control sites (premotor cortex, caudate) in young monkeys performing the delayed response task of a fine motor task. Agonist responses will also be examined after the monkeys have received chronic treatment with reserpine. Research on NE mechanisms continues to examine the hypothesis that alpha-2 agonists selectively improve the cognitive functions of the PFC through actions at a subtype of post-synaptic, alpha-2 receptor in that cortical region. Three related issues are addressed: (1.) Characterization of the alpha-2 agonist response will be continued, including an examination of drug effects on a test of parietal (area 7) function, an NE-rich area that shows age-related deficits. The response of young vs. aged animals to alpha-2 agonist treatment will be compared on a battery of cognitive tasks. (2.) Receptor mechanisms will be further defined by relating drug effects on cognitive function, hypotension and sedation to actions at the cloned alpha-2 subtypes (alpha-2A, alpha-2B, and alpha-2C). Optimal parameters for chronic, oral dosing of the alpha-2A selective agonist, guanfacine, will be determined to identify an appropriate dose regimen for clinical trials in human patients. (3.) The site of cognitive-enhancing effects of alpha-2-agonists in brain will be examined using two different methodologies: (a.) a study will be completed in which alpha-2 agonists are infused into the PFC vs premotor cortex of aged monkeys performing the delayed response test, and (b.) SPECT technology will be utilized to observe clonidine's effects on regional blood flow in aged monkeys performing the delayed response task.

描述（改编自申请人的摘要）：提议的实验将确定延迟响应性能是否得到改善 DA D1 或 D2 激动剂产生的药物作用产生前额皮质（PFC）增强空间工作记忆能力该皮质的变化，或者改善是否源于非特异性变化在性能变量中。这些问题对于D2尤为重要目前认为对 PFC 功能影响不大。将使用两种方法来解决这些问题： 1. D1 和 D2 激动剂（分别为二羟西定和喹吡罗）在老年猴子中以彻底的剂量反应方式进行表征延迟响应任务，其性能随着时间的推移而恶化的任务年龄，以及具有不同认知需求的一系列非 PFC 任务但类似的动机和运动要求，例如延迟反应。这些额外的任务将包括延迟与样本不匹配，视觉辨别力、路线寻找和精细运动技能。任何效果激动剂将受到相同拮抗剂的挑战受体亚型。主要研究者将尝试确定 D1/D2 相互作用通过用另一种亚型的拮抗剂对抗激动剂效应，以及还通过结合 D1 和 D2 激动剂来确定是否联合使用将比单独使用任何一种激动剂带来更大的改善。 2. D1或D2化合物将直接注入前额皮质幼猴表演时的控制位点（运动前皮层、尾状核）精细运动任务的延迟反应任务。激动剂反应将猴子接受长期治疗后也要进行检查利血平。 NE 机制的研究继续检验以下假设： α2激动剂选择性改善前额皮质的认知功能通过突触后α-2受体亚型的作用皮质区。解决了三个相关问题：(1.) 将继续对 α-2 激动剂反应进行表征，包括在顶叶测试中检查药物作用（第 7 区）功能，一个富含 NE 的区域，显示出与年龄相关的缺陷。回应将比较年轻动物与老年动物接受 α-2 激动剂治疗的情况一系列认知任务。 (2.)受体机制将进一步完善定义为药物对认知功能、低血压和对克隆的 alpha-2 亚型（alpha-2A、alpha-2B、和α-2C）。长期口服给药的最佳参数 α-2A选择性激动剂，胍法辛，将被测定以鉴定用于人类患者临床试验的适当剂量方案。 (3.) α-2-激动剂在大脑中增强认知作用的部位使用两种不同的方法进行检查：(a.) 一项研究将完成后，将 α-2 激动剂注入 PFC 与前运动区进行延迟反应测试的老年猴子的皮层，以及（b.） SPECT技术将用于观察可乐定对执行延迟反应任务的老年猴子的局部血流。