Modulation of serotonergic neurotransmission by short- and long-term treatments with sigma ligands
Modulation of serotonergic neurotransmission by short- and long-term treatments with sigma ligands
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DOI：
10.1038/sj.bjp.0704294
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发表时间：
2001-10-01
影响因子：
7.3
通讯作者：
Debonnel, G
中科院分区：
文献类型：
--
作者：
Bermack, JE;Debonnel, G
1 σ受体在1976年首次被描述为阿片受体，但后来被确定为具有两种亚型的不同类别的受体，σ（1）和σ（2）。虽然内源性配体尚未阐明，但最近已经克隆了σ 1受体。2用于测试潜在抗抑郁药的行为模型已显示σ配体产生抗抑郁作用，但其作用机制尚不清楚。3本研究的目的是评估各种σ，在麻醉大鼠中，使用细胞外体内记录，研究了σ（1）配体（+）-喷他佐因和4-羟色胺对中缝背核（DRN）的5-羟色胺（5-HT）神经元放电活性的影响。（N-苄基哌啶-4-基）-4-碘苯甲酰胺（4-IBP）（2 mg/kg·d）处理2天后显著增加5-HT放电活性，并在长期（21天）处理后保持相同的放电速率增加。此外，用（+）-喷他佐辛处理2天和21天所产生的放电率增加可通过同时给予N，N-二丙基-2-（4-甲氧基-3-（2-苯乙氧基）苯基）-乙胺（NE-100）（10 mg kg（-1）天（-1））（一种选择性σ（1）拮抗剂）来防止，证实σ（1）受体对这些作用的调节。相比之下，σ（1）配体（+）-N-环丙基甲基-N-甲基-1，4-二苯基-1-1-乙基-丁-3-烯-1-基胺盐酸盐（JO-1784）和2-（4-吗啉代乙基1-苯基-环己烷-1-羧酸酯盐酸盐（PRE-084）没有影响。5在用（+）-喷他佐因处理21天后，每个轨道发现的神经元数量显著减少。在4-IBP长期治疗后未观察到这种降低，可能代表去极化阻滞。6这些结果表明某些sigma受体对多巴胺能神经传递的调节，并为所报道的“抗抑郁作用”提供了潜在机制，并为sigma（1）配体作为具有快速起效的潜在抗抑郁药提供了证据。
1 Sigma receptors were first described in 1976 as opiate receptors but were later determined to be a distinct class of receptors with two subtypes, sigma(1) and sigma(2). Although the endogenous ligand is yet to be elucidated, the sigma, receptor has recently been cloned.2 Behavioural models used to test potential antidepressants have shown sigma ligands to produce antidepressant effects but their mechanism of action is unknown.3 The goal of the present study was to assess the effects of various sigma, ligands on the firing activity of serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) using extracellular in vivo recordings in anaesthetized rats.4 The sigma(1) ligands (+)-pentazoeine and 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP) (2 mg kg(-1) day(-1)) increased markedly 5-HT firing activity after 2 days of treatment and maintained the same increased firing rate after long-term (21 days) treatments. Furthermore, the increased firing rate produced by 2 and 21 day treatments with (+)-pentazocine was prevented by the coadministration of N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)-thylamine (NE-100) (10 mg kg(-1) day(-1)) a selective sigma(1) antagonist, confirming the sigma, receptor's modulation of these effects. In contrast, the sigma(1) ligands (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784) and 2-(4-morpholinoethyl 1-phenyl-cyclohexane-1-carboxylate hydrochloride (PRE-084) had no effect.5 Following a 21-day treatment with (+)-pentazoeine there was a marked reduction in the number of neurons found per track. This decrease was not seen after chronic treatment with 4-IBP and may represent a depolarization block.6 These results suggest a modulation of serotonergic neurotransmission by some sigma receptors and provide a potential mechanism for the 'antidepressant effects' reported and provide evidence toward sigma(1) ligands as potential antidepressants with a rapid onset of action.