Grigoryan G, Hodges H, Mitchell S, Sinden J D, Gray J A
Department of Psychology, Institute of Psychiatry, De Crespigny Park, London, United Kingdom.
Neurobiol Learn Mem. 1996 Mar;65(2):135-53. doi: 10.1006/nlme.1996.0016.
The separate and combined effects of lesions to the forebrain cholinergic projections system (FCPS) and to dopamine (DA) terminals in the nucleus accumbens (n.acc) were assessed in two water maze tasks: (1) standard acquisition using two trials/day with a 10 min intertrial interval (ITI) for 15 days with the platform in the same position and (2) a working memory task requiring matching to a platform position located by chance on Trial 1, with four trials/day separated by a 30-s ITI and a different platform position on each of 4 days. Effects of nicotine (0.1 mg/kg) were also examined in animals with FCPS, n.acc, and combined lesions in order to determine whether facilatory effects of nicotine in FCPS lesioned animals are mediated by dopamine release in the n.acc. The FCPS and combined lesion groups were impaired in both tasks, but the combined lesion group was substantially worse than animals with FCPS lesions alone. The n.acc lesion group did not differ from controls. Nicotine did not affect acquisition in either the FCPS or combined lesion group, but impaired learning in animals with n.acc lesions. In the working memory task nicotine exerted a nonspecific facilatory effect in the FCPS and combined lesion groups, by reducing latency to find the platform both on the first trial and on the subsequent matching to position trials. Choline acetyltransferase (ChAT) activity was reduced in hippocampus and cortex in the FCPS lesion group, whereas DA levels in n.acc were increased. Conversely, in the n.acc lesion group accumbal DA levels were reduced, while cortical and hippocampal ChAT activity was increased, suggesting that reciprocal changes were induced by the separate lesions. However the combined lesion group showed mixed and more widespread effects; ChAT activity was unaltered in cortex and substantially reduced in hippocampus, and DA levels were reduced in both n.acc and caudate. The results indicate that combined FCPS and n.acc lesions impair spatial learning and working memory far more severely than FCPS lesions alone, although this does not reflect simple additive reductions in DA and ChAT activity. Nicotine improved spatial search strategy, and effect detected in the in the working memory task with daily changes in platform position, rather than in the standard acquistion task, but did not appear specifically to improve working memory. Since the facilitatory effect of nicotine was seen in both FCPS and combined lesion groups, the findings suggest that nicotine-induced improvements do not depend on accumbal DA release.
在前脑胆碱能投射系统（FCPS）和伏隔核（n.acc）多巴胺（DA）终末受损的情况下，通过两个水迷宫任务评估了它们单独及联合损伤的影响：（1）标准习得任务，每天进行两次试验，试验间隔（ITI）为10分钟，持续15天，平台位置固定；（2）工作记忆任务，要求在第1次试验中找到随机放置的平台位置，并在接下来的试验中与之匹配，每天进行4次试验，ITI为30秒，且在4天内每天平台位置不同。还研究了尼古丁（0.1mg/kg）对FCPS、n.acc及联合损伤动物的影响，以确定尼古丁对FCPS损伤动物的促进作用是否由n.acc中的多巴胺释放介导。FCPS损伤组和联合损伤组在两项任务中均受损，但联合损伤组比仅FCPS损伤的动物严重得多。n.acc损伤组与对照组无差异。尼古丁对FCPS损伤组或联合损伤组的习得均无影响，但损害了n.acc损伤动物的学习。在工作记忆任务中，尼古丁在FCPS损伤组和联合损伤组中产生了非特异性促进作用，缩短了首次试验及后续位置匹配试验中找到平台的潜伏期。FCPS损伤组海马和皮质中的胆碱乙酰转移酶（ChAT）活性降低，而n.acc中的DA水平升高。相反，n.acc损伤组伏隔核DA水平降低，而皮质和海马ChAT活性升高，表明单独损伤诱导了相互的变化。然而，联合损伤组表现出混合且更广泛的影响；皮质中ChAT活性未改变，海马中ChAT活性显著降低，n.acc和尾状核中的DA水平均降低。结果表明，FCPS和n.acc联合损伤比单独的FCPS损伤更严重地损害空间学习和工作记忆，尽管这并不反映DA和ChAT活性的简单相加性降低。尼古丁改善了空间搜索策略，这种作用在平台位置每日变化的工作记忆任务中检测到，而非在标准习得任务中，但似乎并非专门改善工作记忆。由于在FCPS损伤组和联合损伤组中均观察到尼古丁的促进作用，研究结果表明尼古丁诱导的改善不依赖于伏隔核DA释放。
