Hodges H, Sowinski P, Turner J J, Fletcher A
Department of Psychology, Institute of Psychiatry, London, UK.
Psychopharmacology (Berl). 1996 May;125(2):146-61. doi: 10.1007/BF02249414.
The effects of the 5-HT3 receptor antagonists. WAY-100,579 and ondansetron (both at doses of 0.001, 0.01 and 0.1 mg/kg s.c.) and the muscarinic receptor agonist arecoline (1.0 mg/kg s.c.), on spatial learning and memory in the water maze were examined in rats after combined S-AMPA lesions to the nucleus basalis and medial septal brain regions. Lesioned rats showed substantially increased latency to find the submerged platform, and spent less time searching in the correct quadrant, and more time circling the periphery of the pool, relative to controls. Lesioned rats treated with WAY-100,579, ondansetron and arecoline exhibited marked improvement in these parameters of learning relative to lesioned animals, with arecoline-treated animals showing the most substantial recovery. Linear dose-related trends of improvement were seen with both of the 5-HT3 antagonists. In probe trials, testing retention of the platform position 24 and 72 h after the end of training, control rats exhibited substantial superiority relative to lesioned rats in accuracy of search in the training quadrant and former platform area, matched by rats treated with arecoline on the first, and by rats treated with the two higher doses of WAY-100,579 and ondansetron on the second probe trial. These results are consistent with our previous studies which demonstrated that another selective 5-HT3 receptor antagonist. WAY-100,289, significantly reversed the cognitive deficits in water maze performance induced by ibotenic acid lesions of forebrain cholinergic projection system. Therefore, selective 5-HT3 receptor antagonists may provide a novel effective therapy for treating cognitive deficits associated with degeneration of central cholinergic neurones, such as Alzheimer's disease or age-associated memory impairment.
在对大鼠基底核和内侧隔脑区联合给予 S-AMPA 损伤后，研究了 5-HT3 受体拮抗剂 WAY-100,579 和昂丹司琼（均采用皮下注射，剂量分别为 0.001、0.01 和 0.1 mg/kg）以及毒蕈碱受体激动剂槟榔碱（皮下注射，剂量为 1.0 mg/kg）对水迷宫空间学习和记忆的影响。与对照组相比，损伤大鼠找到水下平台的潜伏期显著延长，在正确象限搜索的时间减少，在水池周边绕圈的时间增加。与未治疗的损伤动物相比，接受 WAY-100,579、昂丹司琼和槟榔碱治疗的损伤大鼠在这些学习参数上有显著改善，其中槟榔碱治疗的动物恢复最为明显。两种 5-HT3 拮抗剂均呈现出剂量相关的线性改善趋势。在探测试验中，于训练结束后 24 小时和 72 小时测试平台位置的记忆保持情况，对照组大鼠在训练象限和原平台区域的搜索准确性方面相对于损伤大鼠具有显著优势，在第一次探测试验中槟榔碱治疗的大鼠以及在第二次探测试验中接受两种较高剂量 WAY-100,579 和昂丹司琼治疗的大鼠也表现出类似优势。这些结果与我们之前的研究一致，之前的研究表明另一种选择性 5-HT3 受体拮抗剂 WAY-100,289 可显著逆转由前脑胆碱能投射系统的鹅膏蕈氨酸损伤所诱导的水迷宫行为学认知缺陷。因此，选择性 5-HT3 受体拮抗剂可能为治疗与中枢胆碱能神经元退变相关的认知缺陷，如阿尔茨海默病或年龄相关记忆损害，提供一种新的有效治疗方法。
