School of Biological Science and Medical Engineering, BeiHang University, Beijing 100191, China.
Department of Ophthalmology, First Hospital of Jilin University, Changchun 130021, China.
eNeuro. 2023 Jun 27;10(6). doi: 10.1523/ENEURO.0015-23.2023. Print 2023 Jun.
Ketamine, an NMDA antagonist, is widely used in clinical settings. Recently, low-dose ketamine has gained attention because of its promising role as a rapid antidepressant. However, the effects of low-dose ketamine on brain function, particularly higher cognitive functions of primate brains, are not fully understood. In this study, we used two macaques as subjects and found that acute low-dose ketamine administration significantly impaired the ability for arbitrary visuomotor mapping (AVM), a form of associative learning (AL) essential for flexible behaviors, including executions of learned stimuli-response contingency or learning of new contingencies. We conducted in-depth analyses and identified intrinsic characteristics of these ketamine-induced functional deficits, including lowered accuracy, prolonged time for planning and movement execution, increased tendency to make errors when visual cues are changed from trial to trial, and stronger impact on combining associative learning and another key higher cognitive function, working memory (WM). Our results shed new light on how associative learning relies on the NMDA-mediated synaptic transmission of the brain and contribute to a better understanding of the potential acute side effects of low-dose ketamine on cognition, which can help facilitate its safe usage in medical practice.
氯胺酮是一种 NMDA 拮抗剂，广泛应用于临床环境中。最近，低剂量氯胺酮因其作为快速抗抑郁药的潜力而受到关注。然而，低剂量氯胺酮对大脑功能的影响，特别是灵长类动物大脑的高级认知功能，尚未完全了解。在这项研究中，我们使用了两只猕猴作为研究对象，发现急性低剂量氯胺酮给药显著损害了任意视觉运动映射（AVM）的能力，这是一种对于灵活行为至关重要的联想学习（AL）形式，包括执行学习的刺激-反应关联或学习新的关联。我们进行了深入的分析，并确定了这些由氯胺酮引起的功能缺陷的内在特征，包括准确性降低、规划和运动执行所需的时间延长、在视觉线索每次试验发生变化时更倾向于出错，以及对结合联想学习和另一个关键高级认知功能（工作记忆（WM））的影响更强。我们的研究结果揭示了联想学习如何依赖于大脑中的 NMDA 介导的突触传递，并有助于更好地理解低剂量氯胺酮对认知的潜在急性副作用，这有助于促进其在医学实践中的安全使用。
