Acetylcholine plays a pivotal neuromodulatory role in the brain, influencing neuronal activity and cognitive function. Nicotinic receptors, particularly α7 and α4β2 receptors, modulate firing of dorsolateral prefrontal (dlPFC) excitatory networks that underlie successful working memory function. Minimal work however has been done examining working memory following systemic blockade of nicotinic receptor systems in nonhuman primates, limiting the ability to explore interactions of other neuromodulatory influences with working memory impairment caused by nicotinic antagonism. In this study, we investigated working memory performance after administering three nicotinic antagonists, mecamylamine, methyllycaconitine, and dihydro-β-erythroidine, in rhesus macaques tested in a spatial delayed response task. Surprisingly, we found that no nicotinic antagonist significantly impaired delayed response performance compared to vehicle. In contrast, the muscarinic antagonist scopolamine reliably impaired delayed response performance in all monkeys tested. These findings suggest there are some limitations on using systemic nicotinic antagonists to probe the involvement of nicotinic receptors in aspects of dlPFC-dependent working memory function, necessitating alternative strategies to understand the role of this system in cognitive deficits seen in aging and neurodegenerative disease.

乙酰胆碱在大脑中起着关键的神经调节作用，影响神经元活动和认知功能。烟碱样受体，特别是 α7 和 α4β2 受体，调节背外侧前额叶 (dlPFC) 兴奋网络的放电，这是成功工作记忆功能的基础。然而，在非人灵长类动物烟碱受体系统系统性阻断后检查工作记忆的工作很少，限制了探索其他神经调节影响与烟碱拮抗作用引起的工作记忆障碍相互作用的能力。在这项研究中，我们研究了在空间延迟反应任务中测试的恒河猴中施用三种烟碱拮抗剂美加明、甲基乌头碱和二氢-β-赤藓红后的工作记忆性能。出奇，我们发现与载体相比，没有烟碱拮抗剂显着损害延迟反应性能。相比之下，毒蕈碱拮抗剂东莨菪碱确实损害了所有测试猴子的延迟反应性能。这些研究结果表明，使用全身性烟碱拮抗剂来探测烟碱受体在 dlPFC 依赖性工作记忆功能方面的参与存在一些局限性，因此需要采用替代策略来了解该系统在衰老和神经退行性疾病中所见的认知缺陷中的作用。