(-SKF-10,047 AND DEXTROMETHORPHAN AMELIORATE CONDITIONED FEAR STRESS VIA DOPAMINERGIC SYSTEMS LINKED TO PHENYTOIN-REGULATED SIGMA(1) SITES())

Mice exhibited a marked suppression of motility when they were re-plac ed in the same environment in which they had previously received an el ectric footshock. (+)-SKF-10,047 ([2S-(2 alpha,6 ethyl-3-(2-propenyl)- 2,6-methano-3-benzazocin-8-ol hydrochloride; (+)-N-allylnormetazocine hydrochloride) and dextromethorphan, putative sigma receptor agonists, have been reported to reverse this psychological stress-induced motor suppression, defined as conditioned fear stress, through phenytoin-re gulated type a, receptors. In the present study, we investigated the i nvolvement 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 do ses (4 and 20 mg/kg, respectively) when they were co-administered with phenytoin (10 mg/kg), an anticonvulsant drug. The effects were antago nized by the a receptor antagonists, NE-100 -2-[4-methoxy-3-(2-phenyle thoxy)phenyl]-ethylamine monohydrochloride) and BMY-14802 l)-4-(5-fluo ro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride). Furthermore, th e effects of (+)-SKF-10,047 or dextromethorphan in combination with ph enytoin were blocked by the dopamine D-1 receptor antagonist, SCH 2339 0 hyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), and the dopamine D-2 receptor antagonist, (-)-sulpiride, and they were also attenuated by 6-hydroxydopamine-induced lesions of dopaminergic neurons. The amel iorating effects of(+)-SKF-10,047 and dextromethorphan on conditioned fear stress at high doses (5 and 30 mg/kg, respectively) were also blo cked by both the dopamine receptor antagonists. These results suggest that the stress-induced motor suppression is restored by the activatio n of dopaminergic neuronal systems as a result of the stimulation of p henytoin-regulated type sigma(1) receptors.