Antagonism of 5-HT1A receptors uncovers an excitatory effect of SSRIs on 5-HT neuronal activity, an action probably mediated by 5-HT7 receptors
Antagonism of 5-HT1A receptors uncovers an excitatory effect of SSRIs on 5-HT neuronal activity, an action probably mediated by 5-HT7 receptors
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DOI：
10.1111/j.1471-4159.2008.05850.x
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发表时间：
2009-03-01
影响因子：
4.7
通讯作者：
Cremers, Thomas I. F. H.
中科院分区：
文献类型：
--
作者：
Bosker, Fokko J.;Folgering, Joost H. A.;Cremers, Thomas I. F. H.
微透析和电生理学被用来调查是否另一个5-羟色胺（5-HT）受体亚型旁边的5-HT 1A自身受体参与急性效应的选择性5-羟色胺再摄取抑制剂对5-HT神经元的活动。在先前研究的基础上，我们决定研究5-HT 7受体的参与。用特异性5-HT 7拮抗剂SB 258741和推定的5-HT 7激动剂AS 19进行实验。在这项研究中，WAY 100.635用于阻断5-HT 1A受体。SB 258741的全身给药显著降低了选择性5-羟色胺再摄取抑制剂和WAY 100.635联合给药对腹侧海马中细胞外5-HT以及中缝背核中5-HT神经元放电的影响。在微透析研究中，AS 19和WAY 100.635的联合给药显示出对腹侧海马中细胞外5-HT的双相效应，暗示了相反的5-HT 7受体介导的效应。在电生理学实验中，单独全身给药AS 19显示出钟形剂量效应曲线：在较低剂量下适度增加5-HT神经元放电，而在较高剂量下减少。SB 258741能够在低剂量下阻断AS 19的作用。这与AS 19的药理学特征一致，显示出对5-HT 7受体的高亲和力和对5-HT 1A受体的中等亲和力。这些数据支持选择性5-羟色胺再摄取抑制剂对5-HT 7受体介导的5-HT神经元活性的兴奋作用。可以推测，在慢性抗抑郁剂治疗后5-HT神经元放电的恢复（通常归因于单独的5-HT 1A受体的脱敏）实际上是由于5-HT 1A和5-HT 7受体功能之间平衡的改变。
Both microdialysis and electrophysiology were used to investigate whether another serotonin (5-HT) receptor subtype next to the 5-HT1A autoreceptor is involved in the acute effects of a selective serotonin reuptake inhibitor on 5-HT neuronal activity. On the basis of a previous study, we decided to investigate the involvement of the 5-HT7 receptors. Experiments were performed with the specific 5-HT7 antagonist SB 258741 and the putative 5-HT7 agonist AS19. In this study WAY 100.635 was used to block 5-HT1A receptors. Systemic administration of SB 258741 significantly reduced the effect of combined selective serotonin reuptake inhibitor and WAY 100.635 administration on extracellular 5-HT in the ventral hippocampus as well as 5-HT neuronal firing in the dorsal raphe nucleus. In the microdialysis study, co-administration of AS19 and WAY 100.635 showed a biphasic effect on extracellular 5-HT in ventral hippocampus, hinting at opposed 5-HT7 receptor mediated effects. In the electrophysiological experiments, systemic administration of AS19 alone displayed a bell-shaped dose-effect curve: moderately increasing 5-HT neuronal firing at lower doses while decreasing it at higher doses. SB 258741 was capable of blocking the effect of AS19 at a low dose. This is consistent with the pharmacological profile of AS19, displaying high affinity for 5-HT7 receptors and moderate affinity for 5-HT1A receptors. The data are in support of an excitatory effect of selective serotonin reuptake inhibitors on 5-HT neuronal activity mediated by 5-HT7 receptors. It can be speculated, that the restoration of 5-HT neuronal firing upon chronic antidepressant treatment, which is generally attributed to desensitization of 5-HT1A receptors alone, in fact results from a shift in balance between 5-HT1A and 5-HT7 receptor function.