Fishkin R J, Ince E S, Carlezon W A, Dunn R W
Hoechst-Roussel Pharmaceuticals, Inc., Somerville, New Jersey 08876-1258.
Behav Neural Biol. 1993 Mar;59(2):150-7. doi: 10.1016/0163-1047(93)90886-m.
The muscarinic antagonist scopolamine (SCOP; 1.0 mg/kg, ip) impaired both the acquisition of a learning task in the Morris water maze (MWM) and choice accuracy in the T-maze reinforced alternation procedure in rats. Acetylcholinesterase inhibitors (AChEIs) have been shown to attenuate these deficits. D-Cycloserine (DCS), a partial agonist at the strychnine-insensitive glycine site on the N-methyl-D-aspartate (NMDA) receptor complex, was investigated for its effects on SCOP-induced dementia in the MWM and T-maze paradigms. Combined administration of SCOP and DCS (3.0, 10.0, or 30.0 mg/kg, ip; 30 min pretreat) significantly reversed SCOP-induced deficits in the T-maze as measured by percentage correct choices. In addition, DCS (3.0 or 10.0 mg/kg, ip) significantly attenuated SCOP-induced deficits in the MWM as measured by latency to find the submerged platform. For comparison, the long-acting acetylcholinesterase inhibitor galanthamine (GAL) was tested in the T-maze (1.25, 2.5, or 5.0 mg/kg, ip) and the MWM (2.5 or 5.0 mg/kg, ip). GAL attenuated SCOP-induced deficits in both learning and memory models similar to DCS. These data suggest that the strychnine-insensitive partial glycine agonist, D-cycloserine, may be efficacious in disease states of central cholinergic hypofunction such as Alzheimer's disease.
毒蕈碱拮抗剂东莨菪碱（SCOP；1.0毫克/千克，腹腔注射）损害了大鼠在莫里斯水迷宫（MWM）中学习任务的获得以及T迷宫强化交替程序中的选择准确性。乙酰胆碱酯酶抑制剂（AChEIs）已被证明可减轻这些缺陷。D-环丝氨酸（DCS）是N-甲基-D-天冬氨酸（NMDA）受体复合物上对士的宁不敏感的甘氨酸位点的部分激动剂，研究了其对MWM和T迷宫范式中SCOP诱导的痴呆的影响。联合给予SCOP和DCS（3.0、10.0或30.0毫克/千克，腹腔注射；预处理30分钟），通过正确选择百分比测量，显著逆转了SCOP诱导的T迷宫缺陷。此外，通过找到水下平台的潜伏期测量，DCS（3.0或10.0毫克/千克，腹腔注射）显著减轻了SCOP诱导的MWM缺陷。为作比较，长效乙酰胆碱酯酶抑制剂加兰他敏（GAL）在T迷宫（1.25、2.5或5.0毫克/千克，腹腔注射）和MWM（2.5或5.0毫克/千克，腹腔注射）中进行了测试。GAL在学习和记忆模型中减轻了SCOP诱导的缺陷，与DCS相似。这些数据表明，对士的宁不敏感的部分甘氨酸激动剂D-环丝氨酸可能对中枢胆碱能功能减退的疾病状态如阿尔茨海默病有效。
