NEUROPHARMACOLOGIC CHALLENGES IN DEMENTIA

这个项目的总体目标是更好地理解 神经传导的改变是如何改变 痴呆患者的认知和行为。 这 信息可以帮助确定NMDA拮抗剂是否 可能用于治疗神经退行性疾病。 已经有相当多的证据表明， NMDA受体介导长时程 增强，这可能是生理基础， 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在 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，作为一个 兴奋毒素 然而，药物的作用 神经元对人类认知和行为的影响， 这些神经元的损伤与 AD的病理学尚不清楚。 此外，几乎所有 人体试验只涉及急性 NMDA拮抗剂的作用，而不是 长期管理。 这种缺乏知识和 对可能产生的不利影响的担忧抑制了 NMDA拮抗剂的开发 神经保护剂 对某些不良反应的耐受性 这些药物可能会随着持续接触而发展， 可能会阻断GABA-A的副作用 激动剂，也许是通过改变扣带回中的途径 皮层 我们将研究对认知的剂量依赖性影响， 急性和长期输注的行为， 竞争性NMDA受体拮抗剂氯胺酮对老年正常人的影响 受试者和HD和AD患者中使用的剂量为 静脉注射氯胺酮以前被证明是安全的， AD患者 这将有助于我们确定AD是否 患者比其他群体对认知更敏感， NMDA拮抗剂引起的变化。 接下来，我们将比较 急性（1-2小时）和长期（ 至12小时）输注氯胺酮， 进一步研究对这种药物的耐受性 发展起来的 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式避免： 确定用非镇静剂量的 GABA A激动剂苯巴比妥减弱了 氯胺酮引起的行为反应 更好的 理解的认知和行为的影响， 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， 帮助开发方法， 来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.