In vivo screening of cholinergic cognition enhancers

描述（由申请人提供）：本R21申请寻求支持开发一种用于治疗神经精神和神经退行性疾病认知症状的候选治疗方法的新筛选程序。用于检测和表征推定治疗的促认知和促胆碱能特性的生产性和信息性筛选程序仍然很少。拟议的项目旨在研究一种新的体内筛选程序的有用性，用于检测和表征至少部分通过增加前额叶胆碱能活性起作用的认知增强剂。这个过程可以证明由触发注意过程的线索引起的短暂胆碱能活动。候选药物对线索诱发的胆碱能活性（“胆碱能足迹”）的调节作用及其对表现的相关影响被假设为认知增强剂的有效筛选工具。Aim 1的实验将证明不同的“胆碱能足迹”是由主要的参比化合物产生的，包括安非他明、尼古丁、d-环丝氨酸和硫哌丁胺。目的2将证明这种筛选程序可以用来表征和区分抗精神病药物的作用，这些药物被假设在精神分裂症动物模型中表现出不同的促进认知的作用。未来筛选对受体亚型（如胆碱能、去甲肾上腺素能或谷氨酸能受体亚型）具有不同亲和力的化合物，将证明不同的“胆碱能足迹”是由受体亚型选择性化合物产生的。此外，受体亚型选择性化合物的“最佳胆碱能足迹”特征将被定义为进一步筛选的参考。这项研究的长期目标是证明所提出的实验范式可以作为一种有效的筛选测试，用于开发认知增强剂的项目。因此，本研究将有助于开发更有效的临床前策略来检测和开发认知增强剂。与精神分裂症、痴呆和其他神经精神和神经退行性疾病相关的认知障碍治疗的发展一直缺乏信息丰富、有效和富有成效的临床前方法来检测和表征新的治疗方法。由于认知增强剂的开发工作主要集中在调节前脑胆碱能神经传递的药物上，因此本研究旨在开发和验证一种新的通过刺激前额叶胆碱能活动来促进认知增强剂的体内筛选方法。新药发现的发展

DESCRIPTION (provided by applicant): This R21 application seeks support for the development of a novel screening procedure for candidate therapeutics for the treatment of the cognitive symptoms of neuropsychiatric and neurodegenerative disorders. Productive and informative screening procedures for the detection and characterization of the pro-cognitive and pro-cholinergic properties of putative treatments have remained scarce. The proposed project is designed to investigate the usefulness of a new in vivo screening procedure for the detection and characterization of cognition enhancers acting by, at least in part, increasing prefrontal cholinergic activity. This procedure allows the demonstration of transient cholinergic activity evoked by cues triggering attentional processes. The modulatory effects of candidate drugs on cue-evoked cholinergic activity ("cholinergic footprints") and associated effects on performance are hypothesized to serve as effective screening tools for cognition enhancers. The experiments of Aim 1 will demonstrate that differential ""cholinergic footprints"" are generated by major reference compounds, including amphetamine, nicotine, d-cycloserine and thioperamide. Aim 2 will demonstrate that this screening procedure can be employed to characterize and differentiate the effects of antipsychotic drugs hypothesized to exhibit differential pro-cognitive effects in an animal model of schizophrenia. Future screening of compounds with differential affinity to receptor subtypes, such as subtypes of cholinergic, noradrenergic, or glutamatergic receptors, will demonstrate that differential "cholinergic footprints" are generated by receptor subtype-selective compounds. Furthermore, the characteristics of an "optimal cholinergic footprint" for receptor subtype-selective compounds will be defined for use as a reference for further screening. The long-term goal of this research is to demonstrate that the proposed experimental paradigm serves as an effective screening test for use in programs designed to develop cognition enhancers. Thus, this research will contribute to the development of more effective preclinical strategies for the detection and development of cognition enhancers. Relevance The development of treatments for the cognitive impairments associated with schizophrenia, the dementias and other neuropsychiatric and neurodegenerative disorders has been lacking informative, effective and productive preclinical methods for the detection and characterization of new treatments. As efforts to develop cognition enhancers have focused on drugs modulating forebrain cholinergic neurotransmission, the proposed research is designed to develop and validate a new in vivo screening method for cognition enhancers acting via stimulating prefrontal cholinergic activity. The development of new drug finding