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

描述(申请人提供)：认知障碍是阿尔茨海默病和轻微认知障碍的衰弱结果。认知障碍降低了生活质量，增加了治疗成本。认知功能的相对温和增长会导致生活质量的相对较大提高，以及护理成本的较大下降。在开发出针对潜在疾病的治疗方法之前，增强认知功能的姑息治疗将使许多患者受益。这类认知增强剂的一个有希望的药理靶点是γ-氨基丁酸(GABA)A型(GABAA)受体复合体上的苯二氮卓(BZ)结合部位。GABAA-A5 BZ受体(GABAAa5-BZR)的亚型选择性配体已经被开发出来，它主要在记忆功能的重要部位海马区表达。对啮齿动物和非人类灵长类动物记忆测试的研究表明，GABAAa5-BZR反向激动剂改善认知能力，副作用很少。在这项拟议的研究中，8只恒河猴将接受训练，以进行加拿大非人灵长类动物神经心理测试组件的测试。4只猴子还将接受延迟匹配到样本测试的培训，并被植入无线电遥测设备，以测量心血管和呼吸反应，以进行剂量范围研究。剂量范围队列将确定这些化合物在灵长类动物中的有效剂量，并在接受Canab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。新化合物将在小鼠身上进行毒性测试，然后在剂量范围内或经Canab训练的猴子身上进行测试。GABAAa5-BZR配体对猕猴认知功能的影响将通过GABAAa5-BZR激动剂、拮抗剂和反向激动剂的预处理来确定。这些研究将检验这一假设，即GABAAa5-BZR的活动可以双向调节认知，激动剂削弱认知能力，反向激动剂提高认知能力。CANTAB神经心理测试组合的区域特异性也将允许测试GABAAa5-BZR认知调制将在由颞叶大脑结构(即海马体)介导的测试中发生的假设，而不是由额叶皮质结构介导的测试。此外，GABAAa5-BZR反向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造成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，并将进一步发展一类治疗阿尔茨海默病和轻度认知障碍的认知功能障碍的新疗法。

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.