( + )-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated σ₁ 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 σ receptor agonists, but not by other σ 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 σ receptor antagonists, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenytethoxy)phenyl]-ethylamine monohydrochloride) and BMY-14802 (α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol 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 σ receptors, but not of phencyclidine receptors, is involved in the ameliorating effects of ( + )-SKF-10,047 and dextromethorphan on stress-induced motor suppression.