[A study on the pharmacological action of phencyclidine]

Phencyclidine (PCP) produces schizophreniform psychoses in drug abusers and exacerbates symptoms in chronic schizophrenics. Although the exact mechanisms of psychotomimetic effects are unknown, the drug is known to act as an indirect dopamine (DA) agonist by inhibiting neuronal reuptake of DA. The drug is also known to work as a N-methyl-D-aspartate (NMDA) antagonist. Aiming to investigate characteristics of these two properties of PCP in the same experimental system, the effects of PCP on spontaneous and NMDA-induced DA efflux from superfused slices of rat striatum were examined. DA and 3,4-dihydroxyphenylacetic acid (DOPAC) in the superfusate samples were extracted via alumina extraction and measured by high-performance liquid chromatography with electrochemical detection (HPLC-ECD). PCP, at concentrations greater than 1 microM, produced a concentration-dependent increase of the spontaneous efflux of DA. DOPAC efflux was also concentration-dependently increased by PCP. However, PCP inhibited DA efflux induced by NMDA even at a low concentration (0.1 microM), which did not alter the spontaneous efflux of the transmitter. The mode of the inhibition of PCP was shown to be noncompetitive with an estimated IC 50 value of 280 nM. These results indicate that PCP acts simultaneously as a weak indirect DA agonist and as a potent noncompetitive NMDA antagonist. Since psychological change in normal subjects or exacerbation of schizophrenic symptoms has been reported to occur with a small dose of PCP, the psychotomimetic effects of the drug are more likely to be mediated by its interaction with NMDA receptor. The clinical significance of the present study is discussed in relation with the qlutamatergic hypothesis of schizophrenia.