PDF(Pubmed)
Abstract：
Promising new pharmacological strategies for the enhancement of cognition target either nicotinic acetylcholine receptors (nAChR) or N-methyl-D-aspartate receptors (NMDAR). There is also an increasing interest in low-dose combination therapies co-targeting the above neurotransmitter systems to reach greater efficacy over the monotreatments and to reduce possible side effects of high-dose monotreatments. In the present study, we assessed modulatory effects of the α7 nAChR-selective agonist PHA-543613 (PHA), a novel α7 nAChR positive allosteric modulator compound (CompoundX) and the NMDAR antagonist memantine on the in vivo firing activity of CA1 pyramidal neurons in the rat hippocampus. Three different test conditions were applied: spontaneous firing activity, NMDA-evoked firing activity and ACh-evoked firing activity. Results showed that high but not low doses of memantine decreased NMDA-evoked firing activity, and low doses increased the spontaneous and ACh-evoked firing activity. Systemically applied PHA robustly potentiated ACh-evoked firing activity with having no effect on NMDA-evoked activity. In addition, CompoundX increased both NMDA- and ACh-evoked firing activity, having no effects on spontaneous firing of the neurons. A combination of low doses of memantine and PHA increased firing activity in all test conditions and similar effects were observed with memantine and CompoundX but without spontaneous firing activity increasing effects. Our present results demonstrate that α7 nAChR agents beneficially interact with Alzheimer\'s disease medication memantine. Moreover, positive allosteric modulators potentiate memantine effects on the right time and the right place without affecting spontaneous firing activity. All these data confirm previous behavioral evidence for the viability of combination therapies for cognitive enhancement.
摘要：
有望增强认知的新药理学策略靶向烟碱乙酰胆碱受体（nAChR）或N-甲基-D-天冬氨酸受体（NMDAR）。对共同靶向上述神经递质系统的低剂量组合疗法的兴趣也日益增加,以达到超过单调治疗的更大功效并减少高剂量单调治疗的可能副作用。在本研究中,我们评估了α7nAChR选择性激动剂PHA-543613（PHA）的调节作用，一种新型的α7nAChR阳性变构调节剂化合物（CompoundX）和NMDAR拮抗剂美金刚对大鼠海马CA1锥体神经元体内放电活性的影响。应用了三种不同的测试条件：自发发射活动，NMDA诱发的放电活动和ACh诱发的放电活动。结果表明，高剂量但不低剂量的美金刚降低了NMDA诱发的放电活性，低剂量增加了自发和ACh诱发的放电活动。系统地应用PHA可增强ACh诱发的放电活动，而对NMDA诱发的活动没有影响。此外,CompoundX增加了NMDA和ACh诱发的射击活动，对神经元的自发放电没有影响。低剂量的美金刚和PHA的组合在所有测试条件下都增加了放电活性，并且在美金刚和CompoundX的情况下观察到类似的效果，但没有自发放电活性增加的效果。我们目前的结果表明，α7nAChR药物与阿尔茨海默病药物美金刚有益地相互作用。此外，正变构调节剂可在正确的时间和正确的位置增强美金刚的作用，而不会影响自发放电活动。所有这些数据证实了先前的行为证据，证明了认知增强联合疗法的可行性。
