(-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 replace d in the same environment in which they had previously received an ele ctric 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, putat ive 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 antagonis ts, phencyclidine and dizocilpine, attenuated the conditioned fear str ess only at high doses that induced marked hypermotility in non-stress ed mice. The effects of (+)-SKF-10,047 and dextromethorphan, but not p hencyclidine and dizocilpine, on the conditioned fear stress were anta gonized by the sigma receptor antagonists, NE-100 -2-[4-methoxy-3-(2-p henylethoxy)phenyl]-ethylamine monohydrochloride) and BMY-14802 nyl)-4 -(5-fluoro-2-pyrimidinyl)-piperazine-butanol hydrochloride). Interesti ngly, the effects of (+)-SKF-10,047 and dextromethorphan on the stress response were enhanced by combination with phenytoin, an anticonvulsa nt drug, whereas those of (+)-pentazocine, DTG, phencyclidine, and diz ocilpine 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 dextrome thorphan on stress-induced motor suppression.