Bali Zsolt K, Inkeller Judit, Csurgyók Roland, Bruszt Nóra, Horváth Hajnalka, Hernádi István
Department of Experimental Zoology and Neurobiology, and János Szentágothai Research Center, University of Pécs, Hungary.
Department of Experimental Zoology and Neurobiology, and János Szentágothai Research Center, University of Pécs, Hungary.
Behav Brain Res. 2015 Feb 1;278:404-10. doi: 10.1016/j.bbr.2014.10.030. Epub 2014 Oct 30.
The aim of the present study was to compare the cognitive enhancer potential of a recently identified highly selective α7 nicotinic receptor agonist PHA-543613 in scopolamine induced cholinergic and in MK-801 induced glutamatergic transient amnesia models in adult male Wistar rats. Spontaneous alternation paradigm in the T-maze was used as it is considered a reliable measure of spatial working memory and as T-maze performance is highly dependent on the functioning of the hippocampus and the prefrontal cortex. Scopolamine (0.5 mg/kg) and MK-801 (0.1 mg/kg) caused similar decrease of alternation rate and increased locomotion. Prior administration of PHA-543613 (1 or 3 mg/kg) dose dependently and completely reversed scopolamine induced impairment of alternation. However, PHA-543613 had lower efficacy in the MK-801 induced transient amnesia model, as the pharmacologically induced memory deficit was only partially reversed and an inverted U-shaped dose-response was found. PHA-543613 did not modulate either scopolamine or MK-801 induced increased locomotor activity or decreased choice latency. Results suggest that the α7 nicotinic receptor agonist had better efficacy to alleviate working memory deficits of rats caused by cholinergic receptor dysfunction, when NMDA receptors were not primarily targeted. On the other hand, the same memory enhancer strategy through α7 cholinergic receptors was apparently less effective when glutamatergic transmission (via NMDARs) was directly impaired by MK-801 treatment. The present results provide data supporting the need of parallel comprehensive testing of novel drug-candidates for cognitive impairment in distinct preclinical models of memory deficits.
本研究的目的是比较最近鉴定出的高选择性α7烟碱受体激动剂PHA-543613在东莨菪碱诱导的胆碱能性和MK-801诱导的谷氨酸能性成年雄性Wistar大鼠短暂性失忆模型中的认知增强潜力。采用T迷宫中的自发交替范式，因为它被认为是空间工作记忆的可靠指标，并且T迷宫表现高度依赖于海马体和前额叶皮质的功能。东莨菪碱（0.5 mg/kg）和MK-801（0.1 mg/kg）导致交替率类似下降并增加运动能力。预先给予PHA-543613（1或3 mg/kg）剂量依赖性地并完全逆转了东莨菪碱诱导的交替障碍。然而，PHA-543613在MK-801诱导的短暂性失忆模型中的疗效较低，因为药理学诱导的记忆缺陷仅部分得到逆转，并且发现了倒U形剂量反应。PHA-543613既没有调节东莨菪碱或MK-801诱导的运动活性增加，也没有调节选择潜伏期缩短。结果表明，当NMDA受体不是主要靶点时，α7烟碱受体激动剂在减轻胆碱能受体功能障碍引起大鼠的工作记忆缺陷方面具有更好的疗效。另一方面，当MK-801治疗直接损害谷氨酸能传递（通过NMDARs）时，通过α7胆碱能受体的相同记忆增强策略显然效果较差。目前的结果提供了数据，支持在不同的记忆缺陷临床前模型中对新型认知障碍候选药物进行平行综合测试的必要性。
