PHENCYCLIDINE EFFECTS ON CNS AND MEMORY FUNCTIONS

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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.