1. Selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors (SSRIs) cause a greater increase in extracellular 5-HT in the forebrain when the somatodendritic 5-HT1A autoreceptor is blocked. Here, we investigated whether blockade of the terminal 5-HT1B autoreceptor influences a selective 5-HT reuptake inhibitor in the same way, and whether there is an additional effect of blocking both the 5-HT1A and 5-HT1B autoreceptors. 2. Extracellular 5-HT was measured in frontal cortex of the anaesthetized rat by use of brain microdialysis. In vivo extracellular recordings of 5-HT neuronal activity in the dorsal raphe nucleus (DRN) were also carried out. 3. The selective 5-HT reuptake inhibitor, paroxetine (0.8 mg kg-1, i.v.), increased extracellular 5-HT about 2 fold in rats pretreated with the 5-HT1A receptor antagonist, WAY100635. When administered alone neither paroxetine (0.8 mg kg-1, i.v.) nor WAY100635 (0.1 mg kg-1, i.v.) altered extracellular 5-HT levels. 4. Paroxetine (0.8 mg kg-1, i.v.) did not increase 5-HT in rats pretreated with the 5-HT1B/D receptor antagonist, GR127935 (1 mg kg-1, i.v.). GR127935 (1 and 5 mg kg-1, i.v.) had no effect on extracellular 5-HT when administered alone. 5. Interestingly, paroxetine (0.8 mg kg-1, i.v.) caused the greatest increase in 5-HT (up to 5 fold) when GR127935 (1 or 5 mg kg-1, i.v.) was administered in combination with WAY100635 (0.1 mg kg-1, i.v.). Administration of GR127935 (5 mg kg-1, i.v.) plus WAY100635 (0.1 mg kg-1, i.v.) without paroxetine, had no effect on extracellular 5-HT in the frontal cortex. 6. Despite the lack of effect of GR127935 on 5-HT under basal conditions, when 5-HT output was elevated about 3 fold (by adding 1 microM paroxetine to the perfusion medium), the drug caused a dose-related (1 and 5 mg kg-1, i.v.) increase in 5-HT. 7. By itself, GR127935 slightly but significantly decreased 5-HT cell firing in the DRN at higher doses (2.0-5.0 mg kg-1, i.v.), but did not prevent the inhibition of 5-HT cell firing induced by paroxetine. 8. In summary, our results suggest that selective 5-HT reuptake inhibitors may cause a large increase in 5-HT in the frontal cortex when 5-HT autoreceptors on both the somatodendrites (5-HT1A) and nerve terminals (5-HT1B) are blocked. This increase is greater than when either set of autoreceptors are blocked separately. The failure of a 5-HT1B receptor antagonist alone to enhance the effect of the selective 5-HT reuptake inhibitor in our experiments may be related to a lack of tone on the terminal 5-HT1B autoreceptor due to a continued inhibition of 5-HT cell firing. These results are discussed in relation to the use of 5-HT autoreceptor antagonists to augment the antidepressant effect of selective 5-HT reuptake inhibitors.

译文

1.选择性5-羟色胺 (5-HT; 5-羟色胺) 再摄取抑制剂 (SSRIs) 在体细胞肌腱5-HT1A自身受体受阻时,会导致前脑细胞外5-HT的增加。在这里,我们研究了末端5-HT1B自身受体的阻断是否以相同的方式影响选择性5-HT再摄取抑制剂,以及是否存在阻断5-HT1A和5-HT1B自身受体的附加作用。2.使用脑微透析在麻醉的大鼠额叶皮层中测量细胞外5-HT。还进行了中缝背核 (DRN) 中5-HT神经元活性的体内细胞外记录。3.在用5-HT1A受体拮抗剂way100635预处理的大鼠中,选择性5-HT再摄取抑制剂帕罗西汀 (0.8 mg kg-1,i.v.) 使细胞外5-HT增加约2倍。当单独给药时,帕罗西汀 (0.8 mg kg-1,静脉注射) 和WAY100635 (0.1 mg kg-1,静脉注射) 都不会改变细胞外5-HT水平。4.在用5-HT1B/D受体拮抗剂GR127935 (1 mg kg-1,i.v.) 预处理的大鼠中,帕罗西汀 (0.8 mg kg-1,i.v.) 不增加5-HT。GR127935 (1和5 mg kg-1,静脉注射) 单独给药时对细胞外5-HT没有影响。5.有趣的是,当GR127935 (1或5 mg kg-1,静脉注射) 与WAY100635 (0.1 mg kg-1,静脉注射) 联合给药时,帕罗西汀 (0.8 mg kg-1,静脉注射) 引起5-HT的最大增加 (高达5倍)。i.v.)。施用GR127935 (5 mg kg-1,i.v.) 加WAY100635 (0.1 mg kg-1,i.v.) 而不使用帕罗西汀,对额叶皮层的细胞外5-HT没有影响。6.尽管在基础条件下GR127935对5-HT缺乏作用,但当5-HT输出量增加约3倍 (通过向灌注培养基中添加1 microM帕罗西汀) 时,药物导致5-HT剂量相关 (1和5 mg kg-1,静脉注射) 增加。7.就其本身而言,GR127935在较高剂量 (2.0-5.0 mg kg-1,i.v.) 下略微但显著降低DRN中的5-HT细胞放电,但没有阻止帕罗西汀诱导的5-HT细胞放电的抑制。8.总之,我们的结果表明,选择性5-HT再摄取抑制剂可能会导致额叶皮层5-HT大量增加,当体突肌 (5-HT1A) 和神经末梢 (5-HT1B) 上的5-HT自身受体被阻断。此增加大于单独阻塞任一组自身感受器时的增加。在我们的实验中,单独的5-HT1B受体拮抗剂未能增强选择性5-HT再摄取抑制剂的作用,这可能与由于持续抑制5-HT1B自身受体而导致末端5-HT1B自身受体缺乏音调有关。ht细胞放电。讨论了这些结果,这些结果与使用5-HT自身受体拮抗剂来增强选择性5-HT再摄取抑制剂的抗抑郁作用有关。

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