Hodges H, Allen Y, Sinden J, Lantos P L, Gray J A
Department of Psychology, Institute of Psychiatry, Denmark Hill, London, U.K.
Neuroscience. 1991;45(3):609-23. doi: 10.1016/0306-4522(91)90274-r.
The effects of two doses of muscarinic (arecoline and scopolamine) and nicotinic (nicotine and mecamylamine) cholinergic receptor agonists and antagonists on the radial maze errors of rats, performing poorly after ibotenate lesions to the nucleus basalis and medial septal brain regions, were assessed before and after transplantation of cholinergic-rich and -poor fetal grafts, using tasks which measured short- (working) and long-term (reference) spatial and associative memory. Lesioned rats showed improvement with the agonists, and impairment with the antagonists, at low doses which did not affect the performance of controls; these effects were more marked for working than reference memory, especially in the spatial task. The peripherally acting antagonists N-methylscopolamine and hexamethonium did not affect the performance of control or lesioned rats. Effects of the cholinergic probes were re-examined 16 weeks after grafting, in groups with cholinergic-rich grafts to cortex and/or hippocampus which showed functional recovery, and groups with cholinergic-rich grafts to basal forebrain, or cholinergic-poor grafts to basal forebrain, cortex, and hippocampus, which showed no improvement. All lesioned rats, regardless of site, type, or efficacy of transplant, continued to show marked impairment with the antagonists. Poorly performing grafted animals also showed improvement with the agonists. In rats with behaviourally effective cholinergic-rich grafts, arecoline had no effect, but nicotine substantially increased working and reference memory errors, particularly spatial working memory errors. Rats with grafts in both cortex and hippocampus showed the largest increases in errors after nicotine. These results show that lesioned rats were more sensitive to the bi-directional effects of cholinergic receptor ligands than controls, consistent with a role for acetylcholine in the lesion-induced deficits. The predominant effect of drugs on working memory may also be consistent with disruption of acquisition rather than of storage or retrieval processes in memory, and may be related to impairment of attention. The results further show that, despite behavioural recovery, supersensitive responses to cholinergic drugs were not normalized in rats with cholinergic-rich grafts, and that an additive interaction between graft and host may have occurred in response to nicotine.
评估了两种剂量的毒蕈碱型（槟榔碱和东莨菪碱）和烟碱型（尼古丁和美加明）胆碱能受体激动剂及拮抗剂对经鹅膏蕈氨酸损伤基底核和内侧隔脑区后表现不佳的大鼠放射状迷宫错误的影响，这些影响是在移植富含胆碱能和缺乏胆碱能的胎儿移植物前后进行评估的，采用了测量短期（工作）和长期（参考）空间及联想记忆的任务。损伤大鼠在低剂量激动剂作用下表现出改善，在低剂量拮抗剂作用下表现出损伤，而这些低剂量对对照组的表现没有影响；这些效应在工作记忆方面比参考记忆更明显，尤其是在空间任务中。外周作用的拮抗剂N - 甲基东莨菪碱和六甲铵对对照组或损伤大鼠的表现没有影响。在移植16周后，对移植富含胆碱能移植物至皮质和/或海马体且显示功能恢复的组，以及移植富含胆碱能移植物至基底前脑或移植缺乏胆碱能移植物至基底前脑、皮质和海马体且未显示改善的组，重新检查了胆碱能探针的效应。所有损伤大鼠，无论移植部位、类型或效果如何，在拮抗剂作用下仍继续表现出明显损伤。表现不佳的移植动物在激动剂作用下也表现出改善。在行为上有效的富含胆碱能移植物的大鼠中，槟榔碱没有影响，但尼古丁显著增加了工作和参考记忆错误，尤其是空间工作记忆错误。在皮质和海马体都有移植物的大鼠在尼古丁作用后错误增加最多。这些结果表明，损伤大鼠对胆碱能受体配体的双向效应比对照组更敏感，这与乙酰胆碱在损伤诱导的缺陷中起作用一致。药物对工作记忆的主要影响也可能与记忆获取过程的破坏而非存储或检索过程的破坏一致，并且可能与注意力受损有关。结果进一步表明，尽管有行为恢复，但富含胆碱能移植物的大鼠对胆碱能药物的超敏反应并未恢复正常，并且在对尼古丁的反应中可能发生了移植物与宿主之间的相加相互作用。
