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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Evidence for positive allosteric modulation of cognitive-enhancing effects of nicotine by low-dose galantamine in rats
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Evidence for positive allosteric modulation of cognitive-enhancing effects of nicotine by low-dose galantamine in rats

机译：低剂量加兰汀在大鼠尼古丁对尼古丁的积极构建调节的证据

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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.
机译：烟碱型乙酰胆碱受体（nAChR）激动剂的认知增强效应可能在以nAChR功能低下为特征的疾病状态下具有治疗潜力；然而，这些影响往往规模较小，不太可能具有临床意义。nAChR阳性变构调节剂（PAM）的联合给药可通过增强nAChR对激动剂的反应来实现更大的效应。乙酰胆碱酯酶（AChE）抑制剂加兰他敏是低剂量范围内的nAChR PAM。最近的一项临床研究测试了单次小剂量加兰他敏的效果，发现证据表明，与尼古丁在几种认知指标中的一种上存在协同效应。在这项研究中，残留的乙酰胆碱酯酶抑制可能掩盖了其他措施的相互作用。本研究的目的是在啮齿类动物注意力模型中检测缺乏乙酰胆碱酯酶抑制活性的小剂量加兰他敏。加兰他敏（0.03-0.25 mg/kg s.c.）的效果在尼古丁（0.1 mg/kg s.c.）存在和不存在的情况下，在大鼠执行5选择系列反应时间任务时进行了测试，采用受试者内析因设计。单独使用尼古丁或加兰他敏对反应的准确性没有影响。然而，尼古丁和0.06 mg/kg加兰他敏的组合显著提高了准确性。乙酰胆碱酯酶活性分析证实，在这个剂量下，加兰他敏在大脑中没有乙酰胆碱酯酶抑制活性。结果表明，极低剂量的加兰他敏可能会增强或揭示尼古丁的认知增强效应，远远低于人类的典型治疗范围。此外，这些发现为nAChR激动剂和PAM组合策略的认知增强提供了一般性原则证明。

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