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Department of Physiology, University of Maryland School of Medicine, Baltimore 21201.

1. Efflux of 86Rb from synaptosomes prepared from rat forebrain was used to assess voltage-gated changes in K+ permeability in mammalian central nerve terminals. 2. Although they are structurally unrelated to phencyclidine (PCP), the sigma-ligands, N-allyl-normetazocine (NANM; SKF 10,047) and cyclazocine, generalize to PCP in behavioral assays, displace [3H]PCP from a high-affinity binding site in brain, and potently block the same voltage-gated K+ channel as PCP itself. 3. The block of the voltage-gated K+ channel in nerve terminals by NANM and cyclazocine was stereoselective and was unaffected by the opioid antagonist naloxone. Moreover, in our experiments the relative activity of the stereoisomers of NANM and cyclazocine compared favourably with their relative activity in behavioural paradigms and binding assays. 4. Dexoxadrol, the D-isomer of dioxodrol, which produces PCP-like behavioural effects and displaces bound [3H]PCP, was a potent blocker of the PCP-sensitive, voltage-gated K+ channel. The corresponding L-isomer, levoxadrol, which produces morphine-like antinociception and sedation, but does not produce PCP-like behaviour nor displace bound [3H]PCP, was a very weak blocker of the voltage-gated K+ channel. 5. Levoxadrol, but not dexoxadrol, activated a separate K+ channel, as manifested by an increase in 86Rb efflux. This effect was blocked by naloxone. 6. We conclude that one of the PCP-sigma-ligand binding sites in the brain may be associated with the voltage-gated, non-inactivating K+ channel we observe in nerve terminals. Our findings are also consistent with the view that some of the behavioural manifestations of PCP intoxication are mediated by block of presynaptic K+ channels.