Mechanisms mediating the attention-enhancing effects of nicotinic receptor agents

描述(申请人提供)：精神分裂症和阿尔茨海默病等疾病的特点是认知障碍，到目前为止还没有有效的治疗方法。激活烟碱型乙酰胆碱受体(NAChR)的药物可以提高认知能力，最能增强注意力。非选择性nAChR激动剂，如典型的激动剂尼古丁，有广泛的影响范围，包括不想要的副作用。针对nAChR亚型的nAChR激动剂的开发在最大化治疗和减少副作用方面取得的成功有限。本提案的总体目标是产生知识，以此为基础更有针对性地开发具有临床显著认知增强作用的nAChR药物。以前的药物开发工作主要集中在两种表达最广泛的nAChR亚型的激动剂上，反映了这样一个事实，即调节这种抢手效应的具体系统和机制在很大程度上是未知的。该项目旨在确定nAChR试剂增强注意功能的系统和机制。使用类似的人类和啮齿动物范例，我们已经证明对尼古丁增强注意力的作用可靠敏感，该项目包括一系列在健康的从不吸烟的人和大鼠身上进行的相互信息的药理学特征研究。目的1是用变构配体(APL)增强nAChR激动剂的注意增强效应。低剂量尼古丁(作为模型激动剂)和加兰他明的相互作用研究将在人类和大鼠身上进行，并在患有新的、更具选择性的急性早幼粒细胞白血病的大鼠中进行。目的2是评估超低剂量nAChR拮抗剂的注意力增强特性，这是我们先前的临床前研究结果所提出的。在人类和大鼠身上进行的nAChR拮抗剂甲壳胺的研究将伴随着使用更具选择性的nAChR拮抗剂的临床前实验，以及随后的药理相互作用研究，以确定所涉及的次级神经递质系统(S)。目的3是确定介导nAChR激动剂注意增强特性的次级系统(S)。根据我们之前的临床前发现，我们将致力于用一种β肾上腺素受体拮抗剂对抗尼古丁对人类的注意力增强作用。同时进行的临床前实验将旨在用去甲肾上腺素、谷氨酸、GABA能、甘氨酸和组胺能拮抗剂逆转尼古丁的注意效应，剂量本身没有影响。由此产生的知识将使药物开发工作能够专注于在那些调节注意力影响的系统(S)上更有选择性地表达的nAChR亚型。这样的药物将减少不需要的，并可能产生更大的治疗效果。评估APL和超低剂量拮抗剂的益处使nAChR调节策略多样化，目的是产生更大的影响。将人类和啮齿动物的研究结果整合起来，将有助于将其转化为临床实践。总体而言，该项目有望导致nAChR试剂具有更大的临床潜力。

DESCRIPTION (provided by applicant): Diseases such as schizophrenia and Alzheimer's disease are marked by cognitive deficits for which there are to date no effective treatments. Drugs that activate the nicotinic acetylcholine receptor (nAChR) en- hance cognition, most robustly attentional functions. Non-selective nAChR agonists such as the prototypical agonist nicotine have a broad effects profile that includes unwanted side effects. The development of nAChR agonists selective for subtypes of the nAChR has had limited success in maximizing therapeutic and reducing side effects. The overall goal of the present proposal is to generate the knowledge upon which to base a more targeted development of nAChR agents with clinically significant cognitive-enhancing effects. Previous drug development efforts have focused on agonists of the two most widely expressed nAChR subtypes, reflecting the fact that the specific systems and mechanisms mediating the sought-after effects are largely unknown. This project is aimed at identifying the systems and mechanisms through which nAChR agents enhance attentional functions. Employing analogous human and rodent paradigms that we have shown to be reliably sensitive to the attention-enhancing effects of nicotine, this project consists of a series of mutually informative pharmacological characterization studies in healthy human never-smokers and rats. Aim 1 is to potentiate the attention-enhancing effects of nAChR agonism with Allosteric Poten- tiating Ligands (APLs). Interaction studies with low-dose nicotine (as a model agonist) and galantamine will be conducted in humans and rats, and in rats with novel, more selective APLs. Aim 2 is to evaluate the attention-enhancing properties of ultra low-dose nAChR antagonism, suggested by our previous preclinical findings. Studies in humans and rats with the nAChR antagonist mecamylamine will be accompanied by preclinical experiments employing more selective nAChR antagonists, and followed by pharmacological interaction studies to determine the secondary neurotransmitter system(s) involved. Aim 3 is to determine the secondary system(s) mediating the attention-enhancing properties of nAChR agonists. Following our previous preclinical findings, we will aim at antagonizing the attention-enhancing effects of nicotine in humans with a β-adrenoceptor antagonist. Concurrent preclinical experiments will aim at reversing attentional effects of nicotine with noradrenergic, glutamatergic, GABAergic, glycinergic, and histaminergic antagonists at doses devoid of effects by themselves. The resulting knowledge would enable drug development efforts to focus on nAChR subtypes expressed more selectively on those system(s) that mediate effects on attention. Such agents would have reduced unwanted and potentially larger therapeutic effects. Evaluating benefits of APLs and ultra low-dose antagonism diversifies strategies of nAChR modulation with the aim of producing larger effects. The integration of human and rodent findings will facilitate their translation into clinical practice. Overall, the project is expectedto result in nAChR agents with greater clinical potential.