Barnes C A, Meltzer J, Houston F, Orr G, McGann K, Wenk G L
Arizona Research Laboratories, Division of Neural Systems, Memory & Aging, University of Arizona, 384 Life Sciences North Building, Tucson,AZ 85724, USA.
Neuroscience. 2000;99(1):17-23. doi: 10.1016/s0306-4522(00)00180-9.
The function of the cholinergic system is known to change during normal aging and in pathological conditions such as Alzheimer's disease. The present study was designed to assess, within the same group of old animals, the behavioral, electrophysiological and neurochemical effects of chronic treatment with agents that increase the function of the cholinergic system through both muscarinic and nicotinic mechanisms. Doses were determined that produced 60% cholinesterase inhibition by donepezil and galantamine for the old rats. This was chosen to be analogous to therapeutic levels achieved for treatment of human Alzheimer's disease patients with these agents. Because of the well-known age-related changes in spatial memory and hippocampal synaptic plasticity, spatial working memory in the radial eight-arm maze and hippocampal long-term potentiation induction and decay, as well as nicotinic receptor density and affinity, were measured in old rats implanted with minipumps that delivered donepezil, galantamine or saline. There was no effect of drug treatment on baseline synaptic transmission or on the threshold or magnitude of long-term potentiation induction. Both drug treatment groups, however, showed significantly extended long-term potentiation decay times at the perforant path-granule cell synapse over the saline control animals, as measured during the week following induction. Both drugs also elevated the number of nicotinic receptors within the hippocampus and neocortex. This is the first demonstration of cholinergic modulation of synaptic plasticity over the time-course of days. Furthermore, the durability of long-term potentiation was significantly, positively correlated with nicotinic receptor binding in the hippocampus. Chronic treatment with donepezil or galantamine had no significant effect on a well-learned spatial working memory task on the radial maze. These data suggest that the therapeutic doses of cholinesterase inhibitors used to treat patients with Alzheimer's disease may have effects on neurophysiology and neurochemistry that are close to the threshold for producing detectable behavioral improvements.
已知胆碱能系统的功能在正常衰老过程以及诸如阿尔茨海默病等病理状况下会发生变化。本研究旨在评估，在同一组老年动物中，通过毒蕈碱和烟碱机制增强胆碱能系统功能的药物进行长期治疗后的行为学、电生理学和神经化学效应。确定了多奈哌齐和加兰他敏对老年大鼠产生60%胆碱酯酶抑制作用的剂量。选择该剂量是为了使其类似于使用这些药物治疗人类阿尔茨海默病患者所达到的治疗水平。由于空间记忆和海马突触可塑性存在众所周知的与年龄相关的变化，因此在植入了可输送多奈哌齐、加兰他敏或生理盐水的微型泵的老年大鼠中，测量了放射状八臂迷宫中的空间工作记忆以及海马长时程增强的诱导和衰减，以及烟碱受体密度和亲和力。药物治疗对基线突触传递或长时程增强诱导的阈值或幅度没有影响。然而，在诱导后的一周内进行测量时，两个药物治疗组在穿通通路-颗粒细胞突触处的长时程增强衰减时间均显著长于生理盐水对照动物。两种药物还提高了海马和新皮质内烟碱受体的数量。这是首次证明胆碱能对突触可塑性在数天时间进程上的调节作用。此外，长时程增强的持续性与海马中烟碱受体结合显著正相关。用多奈哌齐或加兰他敏进行长期治疗对放射状迷宫中一项已熟练掌握的空间工作记忆任务没有显著影响。这些数据表明，用于治疗阿尔茨海默病患者的胆碱酯酶抑制剂治疗剂量可能对神经生理学和神经化学产生影响，而这些影响接近产生可检测到的行为改善的阈值。
