Phencyclidine and some of its analogues have distinct effects on NMDA receptors of rat hippocampal neurons

Phencyclidine (PCP) is a dissociative anesthetic agent which blocks the excitatory effect of N-methyl-D-aspartate (NMDA) in the central nervous system. To investigate the role of the PCP reactive site in the control of NMDA activation of hippocampal pyramidal cells, we have examined the action of PCP and some of its analogues on the response properties of single NMDA receptors. Application of NMDA (5-15 microM) to outside-out patches of membrane elicited bursts of ion channel openings which were greatly reduced in frequency and duration in the presence of PCP (2.5-10 microM) or m-amino-PCP (2.5-10 microM), a behaviorally active derivative of PCP. These effects of PCP were reversed when the membrane potential was shifted from negative to positive values. Application of the behaviorally inactive agent 1-piperidino-cyclohexanecarbonitrile (greater than or equal to 220 microM) left NMDA-activated currents relatively unaltered. Treatment with another analogue, m-nitro-PCP (5-20 microM), resulted in an unexpected increase in frequency of openings. At a higher concentration (100-300 microM), however, m-nitro-PCP acted like PCP in reducing frequency of opening and channel life-time. Like PCP, these effects of m-nitro-PCP were reversed at positive potentials. Taken together, these results suggest that PCP and its derivatives block the open state of the NMDA channel. Moreover, the dual effect of m-nitro-PCP shows that excitability is not necessarily decreased by PCP analogues but may instead be enhanced depending on modifications of the PCP molecule.