PHENCYCLIDINE EFFECTS ON CNS AND MEMORY FUNCTIONS

该提案的主要目标是使用动物模型作为一种手段， 调查苯环利定（PCP）对 中枢神经系统和学习记忆。 大鼠将被用作 动物模型，因为a）确定适当剂量的 已经开展了用于学习和记忆研究的PCP，B）a 大量的任务，可以评估大鼠的认知功能， 已经开发了在人类身上观察到的平行功能，c）基于 受体结合研究五氯苯酚可能作用于海马体， 新皮层;这两个神经区域已被证明在大鼠中发挥作用， 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。 I. 确定PCP对各种学习和记忆的影响 需要存储时空信息且敏感的任务 海马和新皮质功能障碍 这些任务包括a）记忆 对于空间位置信息，使用延迟的样本匹配或 连续识别记忆过程，B）a）学习和记忆 使用奶酪在开放但有限的空间内的特定空间位置 板（Morris水迷宫的旱地版本）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， 这些任务中的大多数已经开发了测试人类。 二. 确定PCP效应是否主要由NMDA介导 受体，MK 801（NMDA非- 竞争性拮抗剂）、CPP（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）将被 检查并与PCP进行比较。 三. 通过颅内注射更直接地检查 海马或新皮层的神经效应的PCP对学习和记忆。 四. 为了确定长期接触五氯苯酚后是否会出现 学习和记忆的长期变化。 希望这项研究有助于我们了解 五氯苯酚的作用机制，以便随后的治疗策略， 开发这种药物是为了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.