Cognitive-enhancing effects of nicotinic acetylcholine receptor (nAChR) agonists may be of therapeutic potential in disease states characterized by nAChR hypofunction; however, effects tend to be of small magnitude and unlikely clinical significance. The co-administration of a nAChR positive allosteric modulator (PAM) may enable larger effects by potentiating nAChR responses to an agonist. The acetylcholinesterase (AChE) inhibitor galantamine is a nAChR PAM at a low dose range. A recent clinical study testing effects of a single small dose of galantamine found evidence for synergistic effects with nicotine on one of several cognitive measures. In that study, residual AChE inhibition may have obscured interactions on other measures. The present study aimed at examining small galantamine doses devoid of AChE inhibitory activity in a rodent model of attention. The effects of galantamine (0.03–0.25 mg/kg s.c.) were tested in the presence and absence of nicotine (0.1 mg/kg s.c.) in rats performing the 5-Choice Serial Reaction Time Task, employing a within-subject factorial design. There were no effects on response accuracy of either nicotine or galantamine alone. However, the combination of nicotine and 0.06 mg/kg of galantamine significantly enhanced accuracy. AChE activity assays confirmed that, at this dose, galantamine was devoid of AChE inhibitory activity in the brain. The results suggest that cognitive-enhancing effects of nicotine may be potentiated or uncovered by an extremely small dose of galantamine, well below its typical therapeutic range in humans. Furthermore, these findings provide a general proof-of-principle for a nAChR agonist and PAM combination strategy for cognitive enhancement.

烟碱型乙酰胆碱受体 (nAChR) 激动剂的认知增强作用可能对以 nAChR 功能减退为特征的疾病状态具有治疗潜力；然而，影响往往很小，临床意义不大。nAChR 正变构调节剂 (PAM) 的共同给药可以通过增强 nAChR 对激动剂的反应来实现更大的效果。乙酰胆碱酯酶 (AChE) 抑制剂加兰他敏是低剂量范围的 nAChR PAM。最近一项测试单小剂量加兰他敏效果的临床研究发现，尼古丁对几种认知测量中的一种有协同作用的证据。在该研究中，残留的 AChE 抑制可能掩盖了其他措施的相互作用。本研究旨在检查在啮齿动物注意力模型中没有 AChE 抑制活性的小剂量加兰他敏。加兰他敏 (0.03–0.25 mg/kg sc) 的影响在存在和不存在尼古丁 (0.1 mg/kg sc) 的情况下在执行 5-Choice 系列反应时间任务的大鼠中测试，采用受试者内因子设计。单独使用尼古丁或加兰他敏对反应准确性没有影响。然而，尼古丁和 0.06 mg/kg 加兰他敏的组合显着提高了准确性。AChE 活性测定证实，在此剂量下，加兰他敏在大脑中没有 AChE 抑制活性。结果表明，极小剂量的加兰他敏可能会增强或揭示尼古丁的认知增强作用，远低于其在人类中的典型治疗范围。此外，