NEUROPHARMACOLOGIC CHALLENGES IN DEMENTIA

这个项目的总体目标是更好地了解 谷氨酸能传递的改变如何改变 痴呆症患者的认知和行为。这 信息可以帮助确定NMDA拮抗剂 可能被用来治疗神经退行性疾病。 已经有相当多的证据表明， NMDA谷氨酸能受体介导长时程增强 增强，这可能是 学习和记忆。还有相当多的证据表明 含有这些受体的神经元会受到损伤 阿尔茨海默病(AD)和亨廷顿病患者 疾病(HD)，谷氨酸可能有助于 这些疾病的发病机制是通过作为一种 刺激性毒素。然而，谷氨酸能的作用 神经元对人类认知和行为的影响，以及 这些神经元的损伤与血管紧张素转换酶的关系 阿尔茨海默病的症状尚不清楚。此外，几乎所有的 人体试验一直只关注急性呼吸道感染 NMDA拮抗剂的作用而不是 延长服药时间。这种对知识的缺乏和 对可能的不利影响的担忧抑制了 潜在的NMDA拮抗剂的开发 神经保护剂。对某些不良影响的耐受性 这些药物中的一种可能会随着持续接触而发展 有可能阻止GABA-A的不良反应 激动剂，可能通过改变扣带回的通路 大脑皮层。 我们将研究剂量依赖对认知和 急性和长时间输液的行为非 竞争性NMDA拮抗剂氯胺酮在老年正常人群中的应用 受试者和HD和AD患者使用剂量的 静脉注射氯胺酮先前被证明是安全的 阿尔茨海默病患者。这将帮助我们确定AD是否 患者比其他人群对认知更敏感 NMDA拮抗剂引起的变化。接下来，我们将比较 急性(1-2小时)和延长(UP)的影响 至12小时)给AD患者输注氯胺酮至 进一步研究对这种药物的耐受性 发展起来。最后，我们将测试是否不利 这些药物的行为反应可以通过以下方法避免 确定使用非镇静剂量的 GABA A激动剂苯巴比妥减轻不良反应 氯胺酮引起的行为效应。更好的 对认知和行为影响的理解 谷氨酸能拮抗剂将阐明谷氨酸如何 有助于阿尔茨海默病的表达和 帮助开发方法，以便这些药物可以被使用 治疗神经退行性疾病。

The overall goal of this project is to understand better how alterations in glutamatergic transmission modify cognition and behavior in patients with dementia. This information can help determine whether NMDA antagonists might be used to treat neurodegenerative disorders. Already, there is considerable evidence that activation of NMDA glutamatergic receptors mediate long term potentiation, which may be the physiological basis for learning and memory. There is also considerable evidence that neurons containing these receptors are damaged in patients with Alzheimer's disease (AD) and Huntington's disease (HD), and that glutamate may contribute to the pathogenesis of these disorders by acting as an excitotoxin. Nevertheless, the role of glutamatergic neurons upon human cognition and behavior, and the relationship between the damage of these neurons and the symptomatology of AD is unclear. Furthermore, almost all human trials have been concerned only with the acute effects of NMDA antagonists rather than the effects of prolonged administration. This lack of knowledge and concern about possible adverse effects have inhibited the development of NMDA antagonists as potential neuroprotective agents. Tolerance to some adverse effects of these drugs may develop with continued exposure and it may be possible to block adverse effects with GABA-A agonists, perhaps by altering pathways in the cingulate cortex. We will study the dose dependent effects on cognition and behavior of acute and prolonged infusions of the non- competitive NMDA antagonist ketamine in aged normal subjects and in patients with HD and AD using doses of intravenous ketamine previously shown to be safe in patients with AD. This will help us determine whether AD patients are more sensitive than other groups to cognitive changes caused by NMDA antagonists. Next, we will compare the effects induced by acute (1-2 hour) and prolonged (up to 12 hour) infusions of ketamine in patients with AD to examine further the possibility that tolerance to this drug develops. Finally, we will test whether the adverse behavioral reactions of these drugs can be avoided by determining whether treatment with non-sedating doses of the GABA A agonist phenobarbital attenuates the adverse behavioral effects induced by ketamine. A better understanding of the cognitive and behavioral effects of glutamatergic antagonists will clarify how glutamate might contribute to the expression of Alzheimer's disease and help develop approaches so that these drugs could be used to treat neurodegenerative disorders.