Role of channel activation in cognitive enhancement mediated by α7 nicotinic acetylcholine receptors
Role of channel activation in cognitive enhancement mediated by α7 nicotinic acetylcholine receptors
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DOI：
10.1111/j.1476-5381.2009.00426.x
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发表时间：
2009-11-01
影响因子：
7.3
通讯作者：
Gopalakrishnan, Murali
中科院分区：
文献类型：
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作者：
Briggs, Clark A.;Gronlien, Jens Halvard;Gopalakrishnan, Murali
背景和目的：几种α7烟碱型乙酰胆碱受体(NAChR)激动剂已被开发用于治疗认知障碍。然而，激动剂的体内效应很难与体外快速的α7 nAChR脱敏相协调；此外，体外受体效应和体内行为效应之间的相关性也没有被很好地描述。实验方法：鉴定了两种结构相关的α7nAChR激动剂，并将其用于评估行为范式所需的疗效程度。关键结果：NS6784激活人和大鼠的α7nAChR，EC(50)S分别为0.72和0.88mU，表观有效率分别为77%和97%。相比之下，NS6740在α7 nAChR(在卵母细胞中为2%，在GH4C1细胞中为8%)几乎没有效果，尽管它的激动剂样特性是通过添加α7 nAChRs的正变构调节剂或使用缓慢脱敏的α7V274T受体来揭示的。在小鼠抑制回避(IA)记忆保持中，NS6784与60%的部分激动剂A-582941一样提高了表现。相反，NS6740并没有提高表现，而是阻断了A-582941的作用。结论和启示：总的来说，这些发现表明，在IA范式中，行为效应需要一定程度的α7 nAChR激动剂效应，这种行为效应不是由于α7 nAChR脱敏所致。此外，在缺乏对中枢神经系统具有良好穿透作用的α7 nAChR拮抗剂的情况下，该受体的部分激动剂也可用作抑制剂。
Background and purpose:Several agonists of the alpha 7 nicotinic acetylcholine receptor (nAChR) have been developed for treatment of cognitive deficits. However, agonist efficacy in vivo is difficult to reconcile with rapid alpha 7 nAChR desensitization in vitro; and furthermore, the correlation between in vitro receptor efficacy and in vivo behavioural efficacy is not well delineated. The possibility that agonists of this receptor actually function in vivo as inhibitors via desensitization has not been finally resolved.Experimental approach:Two structurally related alpha 7 nAChR agonists were characterized and used to assess the degree of efficacy required in a behavioural paradigm.Key results:NS6784 activated human and rat alpha 7 nAChR with EC(50)s of 0.72 and 0.88 mu M, and apparent efficacies of 77 and 97% respectively. NS6740, in contrast, displayed little efficacy at alpha 7 nAChR (< 2% in oocytes, < 8% in GH4C1 cells), although its agonist-like properties were revealed by adding a positive allosteric modulator of alpha 7 nAChRs or using the slowly desensitizing alpha 7V274T receptor. In mouse inhibitory avoidance (IA) memory retention, NS6784 enhanced performance as did the 60% partial agonist A-582941. In contrast, NS6740 did not enhance performance, but blocked effects of A-582941.Conclusions and implications:Collectively, these findings suggest that a degree of alpha 7 nAChR agonist efficacy is required for behavioural effects in the IA paradigm, and that such behavioural efficacy is not due to alpha 7 nAChR desensitization. Also, a partial agonist of very low efficacy for this receptor could be used as an inhibitor, in the absence of alpha 7 nAChR antagonists with favourable CNS penetration.