(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress via dopaminergic systems linked to phenytoin-regulated sigma(1) sites
(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress via dopaminergic systems linked to phenytoin-regulated sigma(1) sites
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DOI：
10.1016/0014-2999(96)00346-9
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发表时间：
1996-08-08
影响因子：
5
通讯作者：
Nabeshima, T
中科院分区：
文献类型：
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作者：
Kamei, H;Kameyama, T;Nabeshima, T
当小鼠被重新放在先前受到电击的相同环境中时，它们表现出明显的运动抑制。(+)-SKF-10,047([2S-(2α，6 alpha，11R*)]-1，2，3，4，5，6-hexahydro-6，11-dimethyl-3-(2-propenyl)-2，6-methano-3-benzazocin-8-ol盐酸盐；(+)-N-烯丙基去甲氧胞苷盐酸盐)和右美沙芬，可能是西格玛受体激动剂，已被报道通过苯妥英调节的a型受体逆转这种心理应激诱导的运动抑制，被定义为条件性恐惧应激。在本研究中，我们研究了多巴胺能神经元在(+)-SKF-10,047和右美沙芬改善条件性恐惧应激中的作用。(+)-SKF-10,047和右美沙芬在低剂量(分别为4 mg/kg和20 mg/kg)与抗惊厥药物苯妥英钠(10 mg/kg)合用时，可减轻条件性恐惧应激。此作用可被α受体拮抗剂NE-100(N，N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine一盐酸盐)和BMY-14802(a-(4-fluoro-phenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol盐酸盐所拮抗。此外，多巴胺D-1受体拮抗剂SCH 23390(R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2，3，4，5-tetrahydro-1H-3-benzazepine)，和多巴胺D-2受体拮抗剂舒必利可阻断(+)-SKF-10,047或右美沙芬与苯妥英钠合用的作用，并可被6-羟基多巴胺引起的多巴胺能神经元损伤所减弱。(+)-SKF-10,047和右美沙芬在高剂量(分别为5 mg/kg和30 mg/kg)对条件性恐惧应激的改善作用也被两种多巴胺受体拮抗剂阻断。这些结果表明，应激诱导的运动抑制是通过刺激苯妥英调节型Sigma(1)受体而激活多巴胺能神经元系统来恢复的。
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-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-regulated type a, 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 a 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 D-1 receptor antagonist, SCH 23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-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 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.