GABA-A alpha5 cognitive enhancers: pharmacology and neuropsychology in macaques

描述（由申请人提供）：认知障碍是阿尔茨海默病和轻微认知障碍的一种衰弱性结果。认知障碍降低了生活质量，增加了治疗费用。认知功能相对适度的提高会带来生活质量的大幅提高和护理成本的大幅降低。增强认知功能的姑息治疗将使许多患者受益，直到他们的潜在疾病得到治疗。这种认知增强剂的一个有希望的药理学靶点是γ -氨基丁酸（GABA） A型（GABAA）受体复合物上的苯二氮卓类药物（BZ）结合位点。GABAA-a5 BZ受体（GABAAa5- BZr）的亚型选择性配体已经被开发出来，该受体主要在海马中表达，这是记忆功能的重要部位。啮齿类动物和非人灵长类动物的记忆测试研究表明，GABAAa5-BZr逆激动剂可以改善认知，而且几乎没有副作用。在拟议的研究中，将训练8只恒河猴进行CANTAB非人类灵长类动物神经心理测试电池的测试。还将对猴子进行延迟匹配样本测试的训练，并为剂量范围研究植入无线电遥测装置，以测量心血管和呼吸反应。剂量范围队列将确定灵长类动物化合物的有效剂量，并在cantab训练的猴子进行全面认知测试之前筛选产生不良影响的化合物。在对剂量范围或cantab训练的猴子进行测试之前，将对新化合物进行小鼠毒性测试。GABAAa5-BZr配体对猕猴认知功能的影响将通过GABAAa5-BZr激动剂、拮抗剂和逆激动剂的预处理来确定。这些研究将验证GABAAa5-BZr的活性可以双向调节认知的假设，激动剂会损害认知表现，而反向激动剂会增强认知表现。CANTAB神经心理测试组的区域特异性也将允许测试假设，即GABAAa5-BZr认知调节将发生在由颞叶脑结构（即海马）介导的测试中，而不是由额叶皮质结构介导的测试中。此外，GABAAa5-BZr逆激动剂逆转东莨菪碱诱导的认知障碍的能力将决定这些化合物作为治疗阿尔茨海默病引起的认知障碍的潜在有效性。了解GABAAa5-BZr配体的作用对认知的神经药理学、神经心理学和神经解剖学具有重要意义，并将进一步开发一类新的治疗阿尔茨海默病和轻度认知障碍的认知功能障碍的药物。

DESCRIPTION (provided by applicant): Cognitive impairment is a debilitating outcome of Alzheimer's Disease and Minor Cognitive Impairment. Cognitive impairment reduces quality of life and increases treatment costs. Relatively modest increases in cognitive function produce relatively large increases in quality of life and large decreases in cost of care. Palliative treatments enhancing cognitive function would benefit many patients until treatments for their underlying disorders are developed. One promising pharmacological target for such cognitive enhancers is the benzodiazepine (BZ) binding site on the gamma-aminobutyric acid (GABA) type A (GABAA) receptor- complex. Subtype-selective ligands have been developed for the GABAA-a5 BZ receptor (GABAAa5- BZr), which is predominately expressed in the hippocampus, a site important for memory function. Studies in rodent and nonhuman primate memory assays indicate that GABAAa5-BZr inverse agonists improve cognition with few adverse effects. In the proposed studies, 8 rhesus monkeys will be trained to perform tests from the CANTAB nonhuman primate neuropsychological testing battery. 4 monkeys will be also be trained on the delayed-match-to- sample test and implanted with radio-telemetry devices to measure cardiovascular and respiratory responses for dose-ranging studies. The dose-ranging cohort will determine active doses of the compounds in primates and also screen for compounds producing adverse effects prior to full cognitive testing in the CANTAB-trained monkeys. Novel compounds will be tested for toxicity in mice prior to testing in the dose- ranging or CANTAB-trained monkeys. The effects of GABAAa5-BZr ligands on cognitive function in macaques will be determined by pretreatments of GABAAa5-BZr agonists, antagonists and inverse agonists. These studies will test the hypothesis that activity at the GABAAa5-BZr can bi-directionally modulate cognition with agonists impairing cognitive performance and inverse agonists enhancing performance. The regional specificity of the CANTAB neuropsychological test battery will also allow for testing of the hypothesis that GABAAa5-BZr cognitive modulation will occur in tests mediated by temporal brain structures (i.e. the hippocampus) as opposed to tests mediated by frontal cortical structures. In addition, the ability of GABAAa5-BZr inverse agonists to reverse scopolamine-induced cognitive impairment will determine the potential effectiveness of these compounds as treatments for the cognitive impairment produced by Alzheimer's disease. Understanding the effects of GABAAa5-BZr ligands has important implications to the neuro- pharmacology, neuropsychology and neuroanatomy of cognition and will further development of a novel class of therapeutics for cognitive dysfunction in Alzheimer's disease and Minor Cognitive Impairment.