AGING, ATTENTION AND BENZODIAZEPINE RECEPTOR LIGANDS

描述（改编自申请人的摘要）：本研究的目标 建议的研究是确定与年龄相关的神经元基础 注意力障碍，并测试有关的假设， 年龄效应与苯二氮卓受体的相互作用 (BZR)皮质乙酰胆碱（ACh）激动剂和反向激动剂 释放和注意力的能力。 我们以前的数据表明：（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， 分别在测量注意能力的任务中的表现; (2)BZR配体双向调节皮质ACh流出;（3） BZR配体的行为和神经化学作用与年龄相互作用， 皮质胆碱能传入纤维的激活状态;（4）皮质胆碱能传入纤维的激活状态; ACh流出可以在表演动物中测量， 和释放相关;和（5）免疫毒素的皮质输注 192 IgG-皂草素选择性地导致胆碱能传入神经的丧失， 这些病变对乙酰胆碱流出和注意力的影响 能力与年龄的影响相对应。 这些实验 表明关于皮质ACh作用的有效信息需要 在从事行为的动物中ACh流出的测量 激活皮质胆碱能输入的活动。 拟议 研究将测量不同年龄动物的ACh流出量， 执行测量注意力能力或 警觉任务的感觉运动和动机需求。 是 预测警惕性与皮质ACh流出相关， 注意力能力的年龄相关损伤与 减少任务诱发的皮质胆碱能流出。 管理 BZR激动剂的使用会增加年龄的影响。 施用 BZR选择性反向激动剂将促进性能和增强 任务诱导的皮质ACh流出增加，特别是老年人， 动物 ~（192）IgG-皂草素诱导的皮质胆碱能神经元的作用 传入神经阻滞将支持这一假设， 正常老化对皮质ACh影响的模型。 因此 拟议中的研究将测量执行任务的动物体内ACh的释放 因此，将产生关于皮质神经元的作用的有效结论。 年龄对注意力的影响中的乙酰胆碱流出，神经元 老年受试者对认知的敏感性增加的基础 BZR激动剂的作用，以及BZR选择性逆转 作为注意力功能障碍的治疗性治疗的激动剂 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.