AGING, ATTENTION, AND BENZODIAZEPINE RECEPTOR LIGANDS

拟议的研究将重点关注之间的两种不同的相互作用 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 老年人最常用的精神药物，众所周知 损害认知能力及其与年龄相关的相互作用 行为和神经元的变化尚未确定。 的 拟议的研究将检验 BZRa 与衰老作用的假设 协同损害注意力能力。 我们将确定 这种相互作用是否基于 GABA 能神经支配 起源于基底层的胆碱能神经元功能下降 前脑和支配皮层。 二、苯二氮卓受体 发挥与 BZRa 相反作用的配体（即苯二氮卓 受体拮抗剂/部分反向激动剂）已被证明 减轻与干扰相关的行为障碍 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 假设此类治疗的有益行为效果 通过增加皮质乙酰胆碱释放来介导。 这些 效果可能是基于对正常 GABA 胆碱能的抑制 基底前脑的相互作用。 这些实验将采用 用于测试的计算机化操作条件反射技术 不同年龄、全身和不同时期大鼠的注意力能力 对自由活动的动物进行颅内给药，以及 用于测量皮质乙酰胆碱释放的微透析。 因此，拟议的研究将有助于理解 老年人使用 BZRa 的行为和神经元后果， 并将概述小说的行为和神经元潜力 治疗与年龄相关的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.