(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated sigma 1 sites.

Mice exhibited a marked suppression of motility when they were replaced in the same environment in which they had previously received an electric footshock. This psychological stress-induced motor suppression, known as conditioned fear stress, was dose dependently attenuated by (+)-N-allylnormetazocine ((+)-SKF-10,047) and by dextromethorphan, putative sigma receptor agonists, but not by other sigma receptor ligands, (+)-pentazocine and 1,3-di-(2-tolyl)guanidine (DTG). Unlike (+)-SKF-10,047 and dextromethorphan, the non-competitive NMDA receptor antagonists, phencyclidine and dizocilpine, attenuated the conditioned fear stress only at high doses that induced marked hypermotility in non-stressed mice. The effects of (+)-SKF-10,047 and dextromethorphan, but not phencyclidine and dizocilpine, on the conditioned fear stress were antagonized by the sigma receptor antagonists, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2- phenylethoxy)phenyl]-ethylamine monohydrochloride) and BMY-14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine- butanol hydrochloride). Interestingly, the effects of (+)-SKF-10,047 and dextromethorphan on the stress response were enhanced by combination with phenytoin, an anticonvulsant drug, whereas those of (+)- pentazocine, DTG, phencyclidine, and dizocilpine were not. These results suggest that activation of phenytoin-regulated type sigma 1 receptors, but not of phencyclidine receptors, is involved in the ameliorating effects of (+)-SKF-10,047 and dextromethorphan on stress-induced motor suppression.