(+)-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.
Department of Chemical Pharmacology, Meijo University, Nagoya, Japan.
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Kamei
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Kameyama
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Nabeshima
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D003915:Dextromethorphan / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010620:Phenazocine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017480:Receptors, sigma / Q000187:drug effects*; D013312:Stress, Physiological / Q000188:drug therapy*
D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; D010672:Phenytoin; D016291:Dizocilpine Maleate; D003915:Dextromethorphan; C012134:SK&F 10047; D010620:Phenazocine; D010622:Phencyclidine