Piñeyro G, de Montigny C, Blier P
Department of Psychiatry, McGill University, Montreal, Canada.
Neuropsychopharmacology. 1995 Nov;13(3):249-60. doi: 10.1016/0893-133X(95)00109-Q.
The aim of the present study was to characterize the pharmacological profile of 5-hydroxytryptamine (5-HT) receptors modulating 5-HT release in the mesencephalic raphe region. In a first series of experiments, differential normal pulse voltammetry and nafion-coated electrodes were used to measure extracellular 5-HT in the dorsal raphe of anesthesized rats. The intravenous administration of the selective 5-HT1A agonist 8-OH-DPAT (30 micrograms/kg) and the 5-HT1 agonist TFMPP (0.5 mg/kg) reduced the 5-hydroxyindole signal by 23% and 18%, respectively. Pretreatment with the 5-HT1A antagonist (+)WAY100135 (0.5 mg/kg IV) 30 minutes before the injection of the agonists, blocked the effect of 8-OH-DPAT but not that of TFMPP. The effect of TFMPP was blocked by (+/-)mianserin, a drug with high affinity for the rat 5-HT1D receptor, suggesting a role of this receptor subtype in the modulation of 5-HT release at the cell body level of 5-HT neurons. This was confirmed by in vitro superfusion experiments using mesencephalic raphe slices. The prototypical 5-HT1 agonist 5-carboxy-amiditryptamine (5-CT) and the 5-HT1B/1D agonist sumatriptan (1-1,000 nM) induced a concentration-dependent inhibition of the electrically evoked release of [3H]5-HT from preloaded raphe slices. 8-OH-DPAT (100 nM) produced an inhibitory effect similar to that of sumatriptan (100 nM). The selective 5-HT1B agonist CP 93129 (10-10,000 nM), had no effect in raphe slices, but it dose dependently inhibited [3H]5-HT release from hippocampal slices where autoreceptors are of the 5-HT1B subtype. The inhibitory effect of 5-CT was blocked by the 5-HT1/2 antagonist methiothepin (1 microM), the 5-HT1A antagonist S-UH-301 (1 microM), and the 5-HT1B/1D antagonist GR 127935 (1 microM). That of 8-OH-DPAT was blocked by S-UH-301 (1 microM) but not by GR 127935 (1 microM), and that of sumatriptan was blocked by GR 127935 (1 microM) but not by S-UH-301 (1 microM). These results show that, together with 5-HT1A autoreceptors, 5-HT1D receptors negatively modulate the somatodendritic release of 5-HT.
本研究的目的是表征调节中脑缝际区5-羟色胺（5-HT）释放的5-羟色胺（5-HT）受体的药理学特征。在第一系列实验中，采用差分正常脉冲伏安法和涂有萘磺酸钠的电极来测量麻醉大鼠背缝际核中的细胞外5-HT。静脉注射选择性5-HT1A激动剂8-羟基二丙胺基四氢萘（8-OH-DPAT，30微克/千克）和5-HT1激动剂三氟甲基苯哌嗪（TFMPP，0.5毫克/千克）分别使5-羟吲哚信号降低了23%和18%。在注射激动剂前30分钟，静脉注射5-HT1A拮抗剂（+）WAY100135（0.5毫克/千克）预处理，可阻断8-OH-DPAT的作用，但不阻断TFMPP的作用。TFMPP的作用被（+/-）米安色林阻断，米安色林是一种对大鼠5-HT1D受体具有高亲和力的药物，提示该受体亚型在5-HT神经元胞体水平调节5-HT释放中起作用。这一点通过使用中脑缝际核切片的体外灌流实验得到了证实。典型的5-HT1激动剂5-羧酰胺基色胺（5-CT）和5-HT1B/1D激动剂舒马曲坦（1 - 1000纳摩尔）对预加载的缝际核切片中电诱发的[3H]5-HT释放产生浓度依赖性抑制。8-OH-DPAT（100纳摩尔）产生的抑制作用与舒马曲坦（100纳摩尔）相似。选择性5-HT1B激动剂CP 93129（10 - 10000纳摩尔）对缝际核切片无作用，但它对海马切片中[3H]5-HT的释放具有剂量依赖性抑制作用，海马切片中的自身受体属于5-HT1B亚型。5-CT的抑制作用被5-HT1/2拮抗剂甲硫噻平（1微摩尔）、5-HT1A拮抗剂S-UH-301（1微摩尔）和5-HT1B/1D拮抗剂GR 127935（1微摩尔）阻断。8-OH-DPAT的抑制作用被S-UH-301（1微摩尔）阻断，但不被GR 127935（1微摩尔）阻断，舒马曲坦的抑制作用被GR 127935（1微摩尔）阻断，但不被S-UH-301（1微摩尔）阻断。这些结果表明，与5-HT1A自身受体一起，5-HT1D受体对5-HT的树突-胞体释放起负调节作用。
