title: (+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress via dopaminergic systems linked to phenytoin-regulated sigma 1 sites.
abstract: Mice exhibited a marked suppression of motility when they were re-placed in the same environment in which they had previously received an electric footshock. (+)-SKF-10,047 ([2S-(2 alpha, 6 alpha, 11R*)]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-me tha no-3-benzazocin-8-ol hydrochloride; (+)-N-allylnormetazocine hydrochloride) and dextromethorphan, putative sigma receptor agonists, have been reported to reserve this psychological stress-induced motor suppression, defined as conditioned fear stress, through phenytoin-regulated type sigma 1, receptors. In the present study, we investigated the involvement of dopaminergic neurons in the ameliorating effects of (+)-SKF-10,047 and dextromethorphan on conditioned fear stress. (+)-SKF-10,047 and dextromethorphan attenuated conditioned fear stress at low doses (4 and 20 mg/kg, respectively) when they were co-administered with phenytoin (10 mg/kg), an anticonvulsant drug. The effects were antagonized by the sigma receptor antagonists. NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride) and BMY-14802 (a-(4-fluoro-phenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride). Furthermore, the effects of (+)-SKF-10,047 or dextromethorphan in combination with phenytoin were blocked by the dopamine D1 receptor antagonist. SCH 23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine), and the dopamine D2 receptor antagonist, (-)-sulpiride, and they were also attenuated by 6-hydroxydopamine-induced lesions of dopaminergic neurons. The ameliorating effects of (+)-SKF-10,047 and dextromethorphan on conditioned fear stress at high doses (5 and 30 mg/kg, respectively) were also blocked by both the dopamine receptor antagonists. These results suggest that the stress-induced motor suppression is restored by the activation of dopaminergic neuronal systems as a result of the stimulation of phenytoin-regulated type sigma 1 receptors.
authors.affiliation: Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kamei
authors.forename: T
authors.initials: T
authors.lastname: Kameyama
authors.forename: T
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003214:Conditioning, Classical; D003915:Dextromethorphan / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004347:Drug Interactions; D005239:Fear / Q000187:drug effects*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010620:Phenazocine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology*; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D017480:Receptors, sigma / Q000187:drug effects* / Q000502:physiology; D013469:Sulpiride / Q000494:pharmacology
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D017480:Receptors, sigma; D010672:Phenytoin; D003915:Dextromethorphan; C012134:SK&F 10047; D013469:Sulpiride; D016627:Oxidopamine; D010620:Phenazocine