Acute and long-term actions of the antidepressant drug mirtazapine on central 5-HT neurotransmission
Acute and long-term actions of the antidepressant drug mirtazapine on central 5-HT neurotransmission
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DOI：
10.1016/s0165-0327(98)00223-7
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发表时间：
1998-12-01
影响因子：
6.6
通讯作者：
de Montigny, C
中科院分区：
文献类型：
--
作者：
Haddjeri, N;Blier, P;de Montigny, C
Mirtazapine (ORG 3770, Remeron(R)) 是一种新型α(2)-肾上腺素受体拮抗剂，已被证明是一种有效的抗抑郁药物。这些研究的目的是使用大鼠体内电生理学范例来评估米氮平急性和长期治疗对突触前和突触后 α(2)-肾上腺素受体的影响，并确定该药物是否可以调节血清素 (5-HT) 神经传递。米氮平的急性给药导致中缝背侧 5-HT 神经元的放电活动短暂增加。这种效应是通过去甲肾上腺素 (NE) 神经元介导的，因为它在 NE 损伤的大鼠中被消除。事实上，5-HT 神经元放电率的增加是由于蓝斑神经元的 α(2)-肾上腺素能自身受体阻断导致 NE 释放增强而激活的。此外，急性米氮平注射短暂地增强了蓝斑NE神经元的放电活性，并减弱了α(2)-肾上腺素受体激动剂可乐定对这些NE神经元的抑制作用。米氮平持续给药 21 天（5 mg/kg/天，皮下注射，使用微型泵）导致 5-HT 神经元的放电率显着增加（75%），但 NE 神经元的放电率略有增加（30%），并且导致海马 5-HT 末端上的 α(2)-肾上腺素能异质受体脱敏。由于米氮平诱导的 NE 突触可用性增加，导致这些异质受体脱敏，从而使 5-HT 末端免受 NE 对 5-HT 释放的抑制影响。 5-HT 神经元的这些修饰导致突触后 5-HT1A 受体的强直激活增加。后一个结论是基于选择性 5-HT1A 受体拮抗剂 WAY 100635 增强米氮平治疗大鼠背侧海马 CA 和锥体神经元放电活动的能力，但在对照组中则不然。这种增强的 5-HT 神经传递可能是米氮平抗抑郁作用的基础。 (C) 1998 Elsevier Science B.V. 保留所有权利。
Mirtazapine (ORG 3770, Remeron(R)) is a new alpha(2)-adrenoceptor antagonist which has been shown to be an effective antidepressant drug. The aims of the studies were to assess, using an in vivo electrophysiological paradigm in the rat, the effects of acute and long-term treatment with mirtazapine on pre- and postsynaptic alpha(2)-adrenoceptors and to determine whether this drug could modulate serotonin (5-HT) neurotransmission. Acute administration of mirtazapine produced a transient increase of the firing activity of dorsal raphe 5-HT neurons. This effect was mediated via norepinephrine (NE) neurons because it was abolished in NE-lesioned rats. In fact, this increased firing rate of 5-HT neurons was due to their activation by the enhanced release of NE resulting from the blockade of alpha(2)-adrenergic autoreceptors of locus coeruleus neurons. Furthermore, acute mirtazapine injection transiently enhanced the firing activity of locus coeruleus NE neurons and attenuated the suppressant effect of the alpha(2)-adrenoceptor agonist clonidine on these NE neurons. Sustained administration of mirtazapine for 21 days (5 mg/kg/day, s.c., using minipumps) lead to a marked increase in the firing rate of 5-HT neurons (75%) but a more modest increase in the firing rate of NE neurons (30%), as well as to a desensitization of alpha(2)-adrenergic heteroreceptors on 5-HT terminals in the hippocampus. The desensitization of these heteroreceptors, resulting from an increased synaptic availability of NE induced by mirtazapine would free 5-HT terminals from the inhibitory influence of NE on 5-HT release. These modifications of 5-HT neurons lead to an increased tonic activation of postsynaptic 5-HT1A receptors. The latter conclusion was based on the capacity of the selective 5-HT1A receptor antagonist WAY 100635 to enhance the firing activity of dorsal hippocampus CA, pyramidal neurons in mirtazapine-treated rats but not in controls. This enhanced 5-HT neurotransmission may underlie to the antidepressant effect of mirtazapine. (C) 1998 Elsevier Science B.V. All rights reserved.