Phencyclidine selectively inhibits N-methyl-D-aspartate-induced hippocampal [³H]norepinephrine release

We have reported previously that phencyclidine (PCP) antagonizes N-methyl-D-aspartate (NMDA)-induced release of dopamine and acetylcholine from slices of rat striatum and nucleus accumbens. In the present experiments, we examined the effect of PCP on NMDA and kainic acid (KA)-induced release of [³H]norepinephrine (NE) from superfused rat hippocampal slices. NMDA and KA stimulated the efflux of NE with EC₅₀ values of 192 and 245 μM, respectively. The presence of 1.2 mM MgCl₂ in the buffer abolished NMDA-induced release but had little effect on KA-induced release. PCP inhibited the release of [³H]NE induced by 100 μM NMDA with an IC₅₀ of 46 nM, but had no effect on the release of NE stimulated by 300 μM KA. 2-Aminophosphonovalerate antagonized NMDA-induced release, producing a parallel shift to the right in the concentration-response curve. However, PCP shifted the concentration-response curve to the right in a nonparallel fashion. Drugs with PCP-like properties, such as dexoxadrol and cyclazocine, inhibited NMDA-induced release, whereas related drugs such as levoxadrol, ethylketocyclazocine and morphine, which are not PCP-like, had no effect. These data suggest that PCP is a potent, selective, noncompetitive inhibitor of amino acid-induced [³H]NE release and that this action of PCP is mediated through the PCP/sigma receptor.