Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats.
Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats.
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DOI：
10.1371/journal.pone.0027014
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Mikkelsen JD
中科院分区：
文献类型：
--
作者：
Thomsen MS;El-Sayed M;Mikkelsen JD
α7烟碱乙酰胆碱受体（nAChR）是治疗精神分裂症、ADHD和阿尔茨海默病患者认知缺陷的潜在靶点。在此，我们检验了以下假设：α7 nAChR水平的上调是重复给予α7 nAChR激动剂增强和持续促认知效应的基础。我们进一步比较了激动剂与α7 nAChR阳性变构调节剂（PAM）的作用，后者不诱导α7 nAChR上调。使用社会辨别力测试作为短期记忆的测量，我们发现α7 nAChR激动剂A-582941在重复（7次/天）后立即改善短期记忆，但单次给药无效。单次或重复给药后，α7 nAChR PAM PNU-120596和AVL-3288不会立即影响短期记忆。这表明激动剂和PAM的行为效应存在根本差异，可能与临床开发相关。重要的是，A-582941和AVL-3288在重复给药（而非单次给药）后24小时增加短期记忆，表明激动剂和PAM重复给药可能对认知能力产生持续影响。随后的[125 I]-银环蛇毒素放射自显影显示，额叶皮质或海马脑区的α7 nAChR水平与任一化合物的短期记忆之间无直接相关性。此外，A-582941重复给药不影响RIC-3或lynx样基因产物lynx 1、lynx 2、PSCA或Ly 6 H的mRNA表达，已知这些基因产物会影响nAChR功能。总之，α7 nAChR激动剂和PAM在重复给药后均表现出持续的促认知效应，α7 nAChR本身或nAChR功能内源性调节剂水平的改变可能不是该效应的主要原因。
The α7 nicotinic acetylcholine receptor (nAChR) is a potential target for the treatment of cognitive deficits in patients with schizophrenia, ADHD and Alzheimer's disease. Here we test the hypothesis that upregulation of α7 nAChR levels underlies the enhanced and sustained procognitive effect of repeated administration of α7 nAChR agonists. We further compare the effect of agonists to that of α7 nAChR positive allosteric modulators (PAMs), which do not induce upregulation of the α7 nAChR. Using the social discrimination test as a measure of short-term memory, we show that the α7 nAChR agonist A-582941 improves short-term memory immediately after repeated (7× daily), but not a single administration. The α7 nAChR PAMs PNU-120596 and AVL-3288 do not affect short-term memory immediately after a single or repeated administration. This demonstrates a fundamental difference in the behavioral effects of agonists and PAMs that may be relevant for clinical development. Importantly, A-582941 and AVL-3288 increase short-term memory 24 hrs after repeated, but not a single, administration, suggesting that repeated administration of both agonists and PAMs may produce sustained effects on cognitive performance. Subsequent [125I]-bungarotoxin autoradiography revealed no direct correlation between α7 nAChR levels in frontal cortical or hippocampal brain regions and short-term memory with either compound. Additionally, repeated treatment with A-582941 did not affect mRNA expression of RIC-3 or the lynx-like gene products lynx1, lynx2, PSCA, or Ly6H, which are known to affect nAChR function. In conclusion, both α7 nAChR agonists and PAMs exhibit sustained pro-cognitive effects after repeated administration, and altered levels of the α7 nAChR per se, or that of endogenous regulators of nAChR function, are likely not the major cause of this effect.
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影响因子：
5.3
作者：
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通讯作者：
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