(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress via dopaminergic systems linked to phenytoin-regulated σ₁ sites

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-(2α,6α,11R*)]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3- (2-propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride; (+)-N-allylnormetazocine hydrochloride) and dextromethorphan, putative σ receptor agonists, have been reported to reverse this psychological stress-induced motor suppression, defined as conditioned fear stress, through phenytoin-regulated type σ₁ 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 σ 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 σ₁ receptors.