AGING, ATTENTION AND BENZODIAZEPINE RECEPTOR LIGANDS

描述(改编自申请人的摘要)：本报告的目标 建议的研究是确定与年龄相关的神经元基础 注意能力的损害，并测试关于 AGE作用与苯二氮卓类受体的相互作用 皮质乙酰胆碱(ACh)的(BZR)激动剂和反向激动剂 释放和注意力的能力。我们之前的数据表明：(1) 全身或颅内(进入基底前脑)给药 BZR激动剂或反向激动剂损害或促进， 分别是在任务中测量注意能力的表现； (2)BZR配体双向调节皮层ACh外流；(3) BZR配体的行为和神经化学效应与年龄和 大脑皮层胆碱能传入的激活状态；(4)皮质 可以在表演的动物身上测量每个流出的量，该表演 和释放相关；以及(5)免疫毒素的皮质输注 192Ig G-Saporin选择性地导致胆碱能传入的丢失， 这些病变对ACh外流和注意力的影响 能力与衰老的影响相对应。这些实验 表明有关皮质ACh作用有效信息需要 行为活动动物乙酰胆碱酯酶外排的测定 激活皮质胆碱能输入的活动。建议的 研究将测量不同年龄动物的ACh外流 执行测量注意力能力的任务或 警戒任务的感觉运动和动机需求。它是 预测警觉性与皮质ACh流出相关，而且 与年龄相关的注意能力障碍与 任务诱导的皮质胆碱能外流减少。行政管理 BZR激动剂的使用将增强年龄的影响。A的管理 BZR选择性反向激动剂将促进性能和增强 任务诱发的皮质ACh外流增加，特别是在老年人 动物。192IgG-皂苷对大鼠皮质胆碱能神经的影响 去神经识别将支持这样的假设，即这个病变代表 正常衰老对大脑皮层ACh影响的模型。因此， 拟议的研究将测量执行任务的动物的ACh释放 因此，将就皮质激素的作用得出有效的结论 乙酰胆碱外流对注意能力、神经元的影响 老年受试者对认知的敏感性增加的基础 BZR激动剂的作用及对BZR选择性逆转的影响 激动剂作为注意力障碍的治疗药物 与皮质胆碱能功能减退有关。

DESCRIPTION (Adapted from applicant's abstract): The goal of this proposed research is to determine the neuronal basis of the age-related impairments in attentional abilities, and to test hypotheses about the interactions between the effects of age and benzodiazepine receptor (BZR) agonists and inverse agonists on cortical acetylcholine (ACh) release and attentional abilities. Our previous data indicate that: (1) the systemic or intracranial (into the basal forebrain) administration of BZR agonists or inverse agonists impairs or facilitates, respectively, the performance in tasks measuring attentional abilities; (2) BZR ligands bidirectionally modulate cortical ACh efflux; (3) the behavioral and neurochemical effects of BZR ligands interact with age and the activation status of cortical cholinergic afferents; (4) cortical ACh efflux can be measured in performing animals and that performance and release correlate; and (5) cortical infusions of the immunotoxin 192IgG-saporin selectively results in the loss of cholinergic afferents, and that the effects of these lesions on ACh efflux and attentional abilities correspond with the effects of aging. These experiments indicate that valid information about the role of cortical ACh requires the measurement of ACh efflux in animals engaged in behavioral activities which activate cortical cholinergic inputs. The proposed research will measure ACh efflux in differently aged animals while they perform tasks measuring attentional abilities or the effects of the sensorimotor and motivational demands of vigilance tasks. It is predicted that vigilance correlates with cortical ACh efflux, and that the age-related impairments in attentional abilities are associated with a decrease in task- induced cortical cholinergic efflux. Administration of BZR agonists will augment the effects of age. Administration of a BZR selective inverse agonist will facilitate performance and augment the task-induced increase in cortical ACh efflux, particularly in aged animals. The effects of 192IgG-saporin- induced cortical cholinergic deafferentiation will support the hypothesis that this lesion represents a model of the effects of normal aging on cortical ACh. Thus, the proposed research will measure ACh release in task-performing animals and, therefore, will generate valid conclusions on the role of cortical ACh efflux in the effects of age on attentional abilities, the neuronal basis for the increased sensitivity of aged subjects to the cognitive effects of BZR agonists, and on the potential of BZR selective inverse agonists as a therapeutic treatment for the attentional dysfunctions associated with cortical cholinergic hypofunction.