AGING, ATTENTION, AND BENZODIAZEPINE RECEPTOR LIGANDS

拟议的研究将集中在两个不同的相互作用之间 苯二氮卓受体配体与年龄相关的行为和神经元 变化 首先，虽然苯二氮卓受体激动剂（BZRa）是 老年人最常使用的精神药物，并且众所周知 认知能力受损，与年龄相关 行为和神经元的变化还有待鉴定。 的 拟议的研究将测试BZRa和衰老作用的假设， 协同地损害注意力能力。 我们将确定 这种相互作用是否基于GABA能神经支配， 起源于基底节的功能性下降的胆碱能神经元 前脑和支配皮层。 二、苯二氮卓受体 发挥与BZRa相反的作用的配体（i. e.苯二氮卓类 受体拮抗剂/部分反向激动剂）已被证明 减轻与中断相关的行为障碍， 胆碱能系统 拟议的研究将把这些发现扩展到 与正常衰老相关的注意力障碍，并将测试 这种治疗的有益行为效应 是通过增加皮质乙酰胆碱释放来介导的。 这些 作用可能是基于对正常GABA-胆碱能的抑制， 基底前脑的相互作用。 这些实验将采用 计算机操作条件反射技术 不同年龄、全身和 在自由活动的动物中颅内给药，以及 微透析用于测量皮质乙酰胆碱释放。 因此，拟议的研究将有助于了解 在老年人中使用BZRa的行为和神经后果， 并将概述一部小说的行为和神经潜能 治疗年龄相关认知障碍的药理学方法 损伤

The proposed research will focus on two different interactions between benzodiazepine receptor ligands and age-related behavioral and neuronal changes. First, although benzodiazepine receptor agonists (BZRa) are the most often used psychotropic drugs in the elderly, and are known to impair cognitive abilities, their interactions with age-related behavioral and neuronal changes have yet to be characterized. The proposed research will test the hypotheses that BZRa and aging act synergistically to compromise attentional abilities. We will determine whether this interaction is based on the GABAergic innervation of functionally declining cholinergic neurons originating in the basal forebrain and innervating cortex. Second, benzodiazepine receptor ligands that exert effects opposite to BZRa (i. e. , benzodiazepine receptor antagonists/ partial inverse agonists) have been demonstrated to attenuate behavioral impairments associated with disruptions in cholinergic systems. The proposed research will extend these findings to the attentional impairments associated with normal aging, and will test the hypothesis that the beneficial behavioral effects of such treatments are mediated via an increase in cortical acetylcholine release. These effects are presumably based on an inhibition of normal GABA-cholinergic interactions in the basal forebrain. These experiments will employ computerized operant conditioning techniques for the testing of attentional abilities in rats of different ages, systemic and intracranial administration of drugs in freely moving animals, and microdialysis for the measurement of cortical acetylcholine release. Thus, the proposed research will contribute to the understanding of the behavioral and neuronal consequences of the use of BZRa in the elderly, and will outline the behavioral and neuronal potential of a novel pharmacological approach for the treatment of age-related cognitive impairments.