Bartolomeo A C, Morris H, Boast C A
CNS Disorders Division, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000, USA.
Neurobiol Learn Mem. 1997 Nov;68(3):333-42. doi: 10.1006/nlme.1997.3786.
Male Sprague-Dawley rats, preoperatively trained in a 1-h delay non-match-to-position radial maze task, received bilateral stereotaxic injections of a selective cholinotoxin, ethylcholine aziridinium ion (AF64A: 3 nmol/3 microliters/lateral ventricle). Animals treated with AF64A made significantly more total postdelay errors than vehicle controls. Sustained delivery, via miniosmotic pumps, of arecoline (0.1, 0.3, 1, 3, 10, or 30 mg/kg/day sc for 14 days) attenuated the AF64A-induced cognitive impairment in a dose-dependent manner, producing an inverted U-shaped dose-response function which was optimal at 1.0 mg/kg/day. Following these studies, choline acetyltransferase activity was significantly reduced in hippocampi extracted from the AF64A-treated rats, indicating successful cholinotoxicity. This paradigm may be useful as a possible screen for potential Alzheimer's disease therapeutic agents. This conclusion is supported by published reports of beneficial arecoline effects observed following 2-week intravenous infusions in patients with Alzheimer's disease (Soncrant, Raffaele, Asthana, Berardi, Morris, & Haxby, 1993).
雄性斯普拉格-道利大鼠在术前接受了为期1小时的延迟位置不匹配放射状迷宫任务训练，然后通过双侧立体定向注射一种选择性胆碱毒素——氮丙啶乙基胆碱离子（AF64A：3纳摩尔/3微升/侧脑室）。与注射赋形剂的对照组相比，接受AF64A治疗的动物在延迟后的总错误次数显著更多。通过微型渗透泵持续输注槟榔碱（0.1、0.3、1、3、10或30毫克/千克/天，皮下注射，共14天）以剂量依赖的方式减轻了AF64A诱导的认知障碍，产生了一个倒U形剂量反应函数，在1.0毫克/千克/天时最为理想。在这些研究之后，从接受AF64A治疗的大鼠中提取的海马体中胆碱乙酰转移酶活性显著降低，表明胆碱毒性成功诱导。这种范式可能作为一种潜在的阿尔茨海默病治疗药物筛选方法。阿尔茨海默病患者在进行为期2周的静脉输注后观察到槟榔碱有益效果的已发表报告支持了这一结论（Soncrant、Raffaele、Asthana、Berardi、Morris和Haxby，1993年）。
