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.当抑制体树突状5-HT1A自体受体时,选择性5-羟色胺(5-HT; 5-羟色胺)再摄取抑制剂(SSRIs)导致前脑细胞外5-HT的增加。在这里,我们调查了终端5-HT1B自身受体的阻断作用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自身受体的其他作用。 2.通过使用脑微透析在麻醉的大鼠的额皮质中测量细胞外5-HT。还进行了背缝核(DRN)中5-HT神经元活性的体内细胞外记录。 3.选择性5-HT再摄取抑制剂帕罗西汀(0.8mg kg-1,静脉内)在用5-HT1A受体拮抗剂WAY100635预处理的大鼠中使细胞外5-HT增加约2倍。当单独给药时,帕罗西汀(0.8 mg kg-1,i.v.)和WAY100635(0.1 mg kg-1,i.v.)均未改变细胞外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.)不会增加5-HT。单独给药时,GR127935(1和5 mg kg-1,静脉内)对细胞外5-HT无效。 5.有趣的是,当GR127935(1或5 mg kg-1,iv)与WAY100635(0.1 mg)联合使用时,帕罗西汀(0.8 mg kg-1,iv)引起5-HT的最大增加(最多5倍)。千克-1,iv)。不含帕罗西汀的GR127935(5 mg kg-1,i.v.)加上WAY100635(0.1 mg kg-1,i.v.)的给药对额皮质中的细胞外5-HT没有影响。 6.尽管在基本条件下GR127935对5-HT缺乏影响,但当5-HT产量提高了约3倍时(通过向灌注培养基中添加1 microM帕罗西汀),该药物引起了剂量相关(1和5 mg kg-1,iv)5-HT升高。 7.就其本身而言,GR127935在较高剂量(2.0-5.0 mg kg-1,i.v.)的DRN中略微但显着降低了5-HT细胞的发射,但并未阻止帕罗西汀诱导的5-HT细胞发射的抑制。 8.总而言之,我们的研究结果表明,当在肢体树突(5-HT1A)和神经末梢(5-HT1B)上都存在5-HT自身受体时,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。被阻止。该增加量大于分别封闭任一组自动受体时的增加量。在我们的实验中,单独使用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可能与由于持续抑制5-HT细胞而导致末端5-HT1B自体受体缺乏音调有关射击。这些结果与使用5-HT自身受体拮抗剂增强选择性5-HT再摄取抑制剂的抗抑郁作用有关。

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