Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, MD F2-08, PO Box 12233, NC 27709, USA.
Neuropharmacology. 2013 Jul;70:35-42. doi: 10.1016/j.neuropharm.2013.01.004. Epub 2013 Jan 12.
The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in different regions of the brain and is associated with cognitive function as well as anxiety. Agonists and positive allosteric modulators (PAMs) of the α7 subtype of nAChRs have been shown to improve cognition. Previously nicotine, which activates both α7 and non-α7 subtypes of nAChRs, has been shown to have an anxiogenic effect in behavioral tests. In this study, we compared the effects of the α7-selective agonist (PNU-282987) and PAM (PNU-120596) in a variety of behavioral tests in Sprague Dawley rats to look at their effects on learning and memory as well as anxiety. We found that neither PNU-282987 nor PNU-120596 improved spatial-learning or episodic memory by themselves. However when cognitive impairment was induced in the rats with scopolamine (1 mg/kg), both PNU-120596 and PNU-282987 were able to reverse this memory impairment and restore it back to normal levels. While PNU-120596 reversed the scopolamine-induced cognitive impairment, it did not have any adverse effect on anxiety. PNU-282987 on the other hand displayed an increase in anxiety-like behavior at a higher dose (10 mg/kg) that was significantly reduced by the serotonin 5-HT₁a receptor antagonist WAY-100135. However the α7 receptor antagonist methyllycaconitine was unable to reverse these anxiety-like effects seen with PNU-282987. These results suggest that α7 nAChR PAMs are pharmacologically advantageous over agonists, and should be considered for further development as therapeutic drugs targeting the α7 receptors.
α7 型烟碱型乙酰胆碱受体 (nAChR) 在大脑的不同区域高度表达，与认知功能以及焦虑有关。α7 型 nAChR 的激动剂和正变构调节剂 (PAMs) 已被证明可改善认知。先前，激活α7 和非α7 型 nAChR 的尼古丁在行为测试中显示出焦虑作用。在这项研究中，我们比较了 α7 选择性激动剂 (PNU-282987) 和 PAM (PNU-120596) 在各种 Sprague Dawley 大鼠行为测试中的作用，以观察它们对学习和记忆以及焦虑的影响。我们发现，PNU-282987 和 PNU-120596 本身都不能改善空间学习或情景记忆。然而，当用东莨菪碱 (1 mg/kg) 诱导大鼠认知障碍时，PNU-120596 和 PNU-282987 都能够逆转这种记忆障碍，并使其恢复正常水平。虽然 PNU-120596 逆转了东莨菪碱引起的认知障碍，但它对焦虑没有任何不良影响。另一方面，PNU-282987 在较高剂量 (10 mg/kg) 时表现出焦虑样行为增加，这种增加被 5-羟色胺 5-HT₁a 受体拮抗剂 WAY-100135 显著降低。然而，α7 受体拮抗剂甲基六氢烟碱不能逆转 PNU-282987 引起的这些焦虑样效应。这些结果表明，α7 nAChR PAMs 在药理学上优于激动剂，并且作为针对α7 受体的治疗药物，应考虑进一步开发。
