Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA.
Small Animal Behavior Core Laboratory, Augusta University, Augusta, GA.
Nicotine Tob Res. 2019 Feb 18;21(3):383-394. doi: 10.1093/ntr/nty166.
Interest in nicotinic acetylcholine receptor (nAChR) ligands as potential therapeutic agents for cognitive disorders began more than 30 years ago when it was first demonstrated that the tobacco alkaloid nicotine could improve cognitive function in nicotine-deprived smokers as well as nonsmokers. Numerous animal and human studies now indicate that nicotine and a variety of nAChR ligands have the potential to improve multiple domains of cognition including attention, spatial learning, working memory, recognition memory, and executive function. The purpose of this review is to (1) discuss several pharmacologic strategies that have been developed to enhance nAChR activity (eg, agonist, partial agonist, and positive allosteric modulator) and improve cognitive function, (2) provide a brief overview of some of the more common rodent behavioral tasks with established translational validity that have been used to evaluate nAChR ligands for effects on cognitive function, and (3) briefly discuss some of the topics of debate regarding the development of optimal therapeutic strategies using nAChR ligands. Because of their densities in the mammalian brain and the amount of literature available, the review primarily focuses on ligands of the high-affinity α4β2* nAChR ("*" indicates the possible presence of additional subunits in the complex) and the low-affinity α7 nAChR. The behavioral task discussion focuses on representative methods that have been designed to model specific domains of cognition that are relevant to human neuropsychiatric disorders and often evaluated in human clinical trials.
The preclinical literature continues to grow in support of the development of nAChR ligands for a variety of illnesses that affect humans. However, to date, no new nAChR ligand has been approved for any condition other than nicotine dependence. As discussed in this review, the studies conducted to date provide the impetus for continuing efforts to develop new nAChR strategies (ie, beyond simple agonist and partial agonist approaches) as well as to refine current behavioral strategies and create new animal models to address translational gaps in the drug discovery process.
作为治疗认知障碍的潜在治疗剂，烟碱型乙酰胆碱受体（nAChR）配体的研究兴趣始于 30 多年前，当时首次证明烟草生物碱尼古丁可以改善尼古丁剥夺的吸烟者和非吸烟者的认知功能。现在，大量的动物和人体研究表明，尼古丁和各种 nAChR 配体有可能改善包括注意力、空间学习、工作记忆、识别记忆和执行功能在内的多个认知领域。本文的目的是：（1）讨论几种已开发的增强 nAChR 活性的药理学策略（例如激动剂、部分激动剂和正变构调节剂）和改善认知功能；（2）简要概述一些更常见的具有既定转化有效性的啮齿动物行为任务，这些任务已被用于评估 nAChR 配体对认知功能的影响；（3）简要讨论关于使用 nAChR 配体开发最佳治疗策略的一些有争议的话题。由于其在哺乳动物大脑中的密度和可用文献数量，本文主要集中在高亲和力α4β2* nAChR（“*”表示在该复合物中可能存在其他亚基）和低亲和力α7 nAChR 的配体上。行为任务讨论侧重于旨在模拟与人类神经精神疾病相关的特定认知领域的代表性方法，并且经常在人类临床试验中进行评估。
支持开发各种影响人类的 nAChR 配体的临床前文献不断增加。然而，迄今为止，除了尼古丁依赖之外，没有新的 nAChR 配体被批准用于任何其他疾病。正如本文所讨论的，迄今为止进行的研究为继续努力开发新的 nAChR 策略（即超越简单的激动剂和部分激动剂方法）以及改进当前的行为策略和创建新的动物模型以解决药物发现过程中的转化差距提供了动力。
