PCP AND KETAMINE INHIBIT NON-NMDA GLUTAMATE-RECEPTOR MEDIATED HSP70 INDUCTION

The physiological model for glutamate receptor mediated excitotoxicity entails elevation of intraneuronal calcium levels. Excessive activati on of the NMDA receptor leads to excitotoxicity by prolonged calcium i nflux via its calcium channel. The purpose of this research was to exa mine the mechanism of non-NMDA glutamate receptor mediated excitotoxic ity. Mammalian AMPA receptors do not show significant calcium conducta nce. However, some kainate receptors show significant calcium conducta nce. The hypothesis of this research states that non-NMDA glutamate ag onists (quisqualate (5 mu l of 2 mg/ml i.c.v.), AMPA (4 mu l of 1 mg/m l i.c.v.), and kainate (15 mg/kg i.p.)) produce significant heat shock gene, hsp70, induction via glutamate release with subsequent opening of the NMDA receptor calcium channel. PCP (phencyclidine) and ketamine are noncompetitive blockers of the NMDA calcium channel. They act to prevent significant NMDA receptor excitotoxicity. PCP (20 mg/kg i.p.) and ketamine (60 mg/kg i.p.) both diminished quisqualate and AMPA hsp7 0 induction in the CA1, CA2, CA3 areas of the hippocampus, in the poly morph area of the dentate gyrus, and in the parietal neocortex. PCP si gnificantly (P < 0.05) diminished kainate hsp70 induction only in the CA1 area and the neocortex. Ketamine failed to reduce kainate hsp70 in duction. AMPA receptors appear to result in excitotoxic damage via glu tamate release. Glutamate opens NMDA receptor calcium channels which i ncreases intraneuronal calcium levels. Kainate receptors probably medi ate excitotoxicity via direct calcium conductance with glutamate relea se being important in the CA1 area and neocortex.