PHENCYCLIDINE EFFECTS ON CNS AND MEMORY FUNCTIONS

这项提议的主要目标是利用动物模型作为一种手段 苯环利定(PCP)对小鼠的急性和慢性影响 对中枢神经系统和学习记忆的影响。这只老鼠将被用作 动物模型是因为a)确定适当的剂量 已经进行了学习和记忆研究的PCP，b)a 可以评估大鼠认知功能的大量任务 已经开发出与人类观察到的平行功能，c)基于 受体结合研究PCP可能作用于海马区和 新皮质；在大鼠的两个神经区域中都显示出扮演着 在许多复杂的学习和记忆任务中发挥重要作用。 这里提出的实验是针对四个具体目标的。 I.确定五氯苯酚对多种学习和记忆的影响 需要存储时空信息并具有敏感性的任务 到海马区和新皮质功能障碍。这些任务包括a)存储器 对于空间位置信息，使用延迟的样本匹配或 连续再认记忆程序，b)学习和记忆 在开放但有限的空间中使用奶酪的特定空间位置 板(旱地版的莫里斯水迷宫)任务，c)时间记忆 空间位置列表的顺序，d)空间或 对象的时间配置。此外，类似的程序也适用于 为这些任务中的大多数开发了测试人类的方法。 二、确定PCP效应是否主要由NMDA介导 受体对MK-801学习记忆的影响 竞争性拮抗剂)、CPP(一种NMDA竞争性拮抗剂)和SKF- 10,047(乙状结肠激动剂和NMDA非竞争性拮抗剂) 检测并与PCP进行比较。 III.通过颅内注射更直接地检查 海马区或大脑皮层PCP对学习和记忆的神经影响。 确定长期接触五氯苯酚后是否会有 随后在学习和记忆方面的长期变化。 希望这项研究将有助于我们理解 五氯苯酚的作用机制，以便后续的治疗策略 开发的目的是抵消五氯苯酚对中枢神经系统的潜在有害影响。

The major goal of this proposal is to use an animal model as a means of investigating acute and chronic effects of phencyclidine (PCP) on the central nervous system and on learning and memory. The rat will be used as the animal model because a) the determination of the appropriate doses of PCP for the learning and memory studies have already been carried out, B) a large number of tasks which can assess cognitive functions in rats that parallel functions observed with humans have been developed, c) based on receptor binding studies PCP is likely to act on the hippocampus and neocortex; both neural regions have been shown in the rat to play an important role in a number of complex learning and memory tasks. The experiments proposed here are directed toward four specific aims. I. To determine the effects of PCP on a variety of learning and memory tasks that require memory for spatio-temporal information and are sensitive to hippocampal and neocortical dysfunction. These tasks include a) memory for spatial location information using a delayed matching-to-sample or a continuous recognition memory procedure, b) learning and memory for a specific spatial location within an open but limited space using a cheese board (dry land version of Morris' water maze) task, c) memory for temporal order of a list of spatial locations, d) memory performance for spatial or temporal configurations of objects. Furthermore, analogous procedures for testing humans have been developed for most of these tasks. II. To ascertain whether PCP effects are primarily mediated by NMDA receptors, the effects on learning and memory of MK 801 (a NMDA non- competitive antagonist), CPP (a NMDA competitive antagonist), and SKF- 10,047 (a sigmoid agonist and NMDA non-competitive antagonist) will be examined and compared with PCP. III. To examine more directly via intracranial injections into the hippocampus or neocortex the neural effects of PCP on learning and memory. IV. To ascertain whether following chronic exposure to PCP there will be subsequent long-term changes in learning and memory. It is hoped that this research will help in our understanding of the mechanisms of action of PCP, so that subsequent treatment strategies can be developed to counteract the potential harmful effects of PCP on the CNS.