AGING, ATTENTION, AND BENZODIAZEPINE RECEPTOR LIGANDS

衰老、注意力和苯二氮卓受体配体

• 批准号: 2051433
• 负责人: MARTIN F SARTER
• 金额: $ 7.58万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2051433
• 关键词: GABA receptor; acetylcholine; aging; attention; benzodiazepine receptor; benzodiazepines; brain metabolism; chlordiazepoxide; cholinergic receptors; dialysis; drug administration routes; high performance liquid chromatography; inhibitor /antagonist; injection /infusion; laboratory rat; operant conditionings; psychopharmacology; stereotaxic techniques

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.

拟议的研究将集中在两种不同的相互作用上 苯二氮卓类受体配体与年龄相关的行为和神经元 改变。首先，尽管苯二氮卓类受体激动剂(BZRa)是 最常在老年人中使用精神药物，并已知 认知能力受损，与年龄相关的相互作用 行为和神经元的变化尚未确定。这个 拟议的研究将检验BZRa和衰老起作用的假设 协同作用来折衷注意力能力。我们将决定 这种相互作用是否基于GABA能神经支配 起源于基底节区的功能性衰退胆碱能神经元 前脑和神经皮质。第二，苯二氮卓类受体 与BZRa相反作用的配体(即苯二氮卓类 受体拮抗剂/部分反向激动剂)已被证明 减轻与精神障碍相关的行为障碍 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 假设这种治疗的有益行为效果 是通过增加皮质乙酰胆碱释放来调节的。这些 这种作用可能是基于对正常的GABA-胆碱能的抑制。 基底前脑中的相互作用。这些实验将使用 用于测试的计算机操作条件调节技术 不同年龄、全身性和全身性的大鼠注意能力 自由活动动物的颅内给药，以及 微透析法测定皮质乙酰胆碱释放。 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， 并将勾勒出一种新的行为和神经元潜力 治疗年龄相关性认知障碍的药理学方法 减损。