Distinct modulatory roles of sigma receptor subtypes on glutamatergic responses in the dorsal hippocampus
Distinct modulatory roles of sigma receptor subtypes on glutamatergic responses in the dorsal hippocampus
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DOI：
10.1002/syn.20085
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发表时间：
2005-01-01
期刊：
影响因子：
2.3
通讯作者：
Debonnel, G
中科院分区：
文献类型：
--
作者：
Bermack, JE;Debonnel, G
先前已经显示0配体调节背侧海马中的N-甲基-D-天冬氨酸（NMDA）应答，使得低剂量的0激动剂剂量依赖性地增强应答。最近对σ配体4-IBP的研究发现，在中缝背核（DRN）中5-HT放电活性的调节中，σ配体4-IBP与σ配体（+）-喷他佐辛和DTG的作用不同，因为其作用不被逆转（+）-喷他佐辛或DTG的作用的σ拮抗剂阻断。因此，本研究开始使用σ配体活性的海马范例来表征4-IBP对σ受体的作用。有趣的是，我们发现，在50%的神经元记录，4-IBP（20微克/公斤静脉注射），产生了NMDA和使君子酸（QUIS）诱导的反应增强。在另外50%的神经元中，4-IBP产生QUIS和NMDA反应的衰减。σ 1拮抗剂NE-100阻断4-IBP诱导的还原，而非选择性σ 1拮抗剂氟哌啶醇阻断4-1BP诱导的所有反应。这些数据表明，在该模型中，4-1BP可能作为σ受体的激动剂或反向激动剂。此外，在4-1BP引起放电活动衰减的组中，对NMDA和QUIS的初始反应更高。这表明4-IBP对海马体中的多巴胺能神经传递的调节作用，其似乎涉及由不同的σ 1受体亚型介导的两种不同的途径，NE-100和氟哌啶醇敏感的σ 1受体，以及NE-100不敏感的氟哌啶醇敏感的σ 1受体。这种调节作用对涉及海马体中的神经递质传递的疾病有影响。(C)2004 Wiley-Liss，Inc.
Sigma ligands have been previously shown to modulate the N-methyl-D-aspartate (NMDA) response in the dorsal hippocampus, such that low doses of sigma agonists dose-dependently potentiate the response. Recent studies with the sigma ligand 4-IBP found it to act differently from the sigma ligands (+)-pentazocine and DTG in the modulation of 5-HT firing activity in the dorsal raphe nucleus (DRN), as its effects were not blocked by the sigma antagonists which reversed those of (+)-pentazocine or DTG. Thus, this study set out to characterize 4-IBP's action at sigma receptors using the hippocampal paradigm of sigma ligand activity. Interestingly, we found that in 50% of the neurons recorded, 4-IBP (20 mug/kg i.v.) produced a potentiation of both NMDA- and quisqualate (QUIS)-induced responses. In the other 50% of neurons, 4-IBP produced an attenuation of both QUIS and NMDA responses. The sigma, antagonist NE-100 blocked the reduction induced by 4-IBP, while the nonselective sigma antagonist haloperidol blocked all responses induced by 4-1BP. These data suggest that, in this model, 4-1BP may be acting as an agonist or inverse agonist of sigma receptors. Furthermore, the initial responses to NMDA and QUIS were higher in the group in which 4-1BP induced an attenuation of the firing activity. This suggests a modulatory role for 4-IBP on glutamatergic neurotransmission in the hippocampus, which appears to involve two distinct pathways, mediated by different sigma, receptor subtypes, an NE-100 and haloperidol-sensitive sigma, receptor, and an NE-100-insensitive, haloperidol-sensitive sigma, receptor. This modulatory role has implications for disorders that involve glutamatergic transmission in the hippocampus. (C) 2004 Wiley-Liss, Inc.