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）：拟议的实验将确定延迟响应绩效的改善由DA D1或D2激动剂产生的是由毒品作用在前额叶皮层（PFC）增强空间工作记忆能力该皮质的改进是由非特异性变化引起的在性能变量中。这些问题对于D2尤其重要化合物，目前认为对PFC功能的影响很小。将使用两种方法来解决以下问题： 1。D1和D2激动剂（分别为二羟化和奎因梭）将在老年猴子上以彻底的剂量反应方式来表征延迟响应任务，其性能随着绩效恶化而随着年龄，以及一系列具有不同认知需求的非PFC任务但是类似的动机和运动要求，例如延迟响应。这些其他任务将包括延迟的非匹配样本，视觉歧视，路线查找和精细的运动技能。任何效果激动剂将受到同一对抗者的挑战受体亚型。主要研究者将尝试识别D1/D2的交互通过与另一个亚型的拮抗剂对抗激动剂作用，然后还通过将D1和D2激动剂结合起来确定是否是否组合将比单独使用任何一种激动剂会导致更大的进步。 2。D1或D2化合物将直接注入前额叶皮层和对照地点（在年轻猴子表演的幼猴的控制位点（尾状）精细电机任务的延迟响应任务。激动剂的反应会在猴子接受了长期治疗后，还可以检查利比恩。 NE机制的研究继续研究以下假设。 alpha-2激动剂有选择地改善PFC的认知功能通过以突触后，α-2受体的亚型的作用皮质区域。解决了三个相关问题：（1.） α-2激动剂反应的表征将继续包括对顶壁测试的药物作用检查（第7区）功能，一个富含NE的区域，显示与年龄相关的缺陷。反应将比较年轻动物与老年动物到α-2激动剂治疗在一系列认知任务上。（2.）受体机制将进一步由药物对认知功能，低血压和克隆alpha-2亚型的动作镇静作用（alpha-2a，alpha-2b，和alpha-2c）。慢性，口服剂量的最佳参数 Alpha-2a选择性激动剂，瓜辛（Guanfacine）将被确定以识别适用于人类患者临床试验的适当剂量方案。（3.） Alpha-2激动剂在大脑中的认知增强作用部位将使用两种不同的方法检查：（a。）研究将是完成的Alpha-2激动剂被注入PFC VS Prepor 进行延迟响应测试的老化猴子的皮质，（b。） SPECT技术将被用来观察可乐定的影响老化猴子的区域血流执行延迟的响应任务。