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首页> 外文期刊>European Journal of Pharmacology: An International Journal >LY393558, a 5-hydroxytryptamine reuptake inhibitor and 5-HT(1B/1D) receptor antagonist: effects on extracellular levels of 5-hydroxytryptamine in the guinea pig and rat.
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LY393558, a 5-hydroxytryptamine reuptake inhibitor and 5-HT(1B/1D) receptor antagonist: effects on extracellular levels of 5-hydroxytryptamine in the guinea pig and rat.

机译：LY393558，一种5-羟色胺再摄取抑制剂和5-HT（1B / 1D）受体拮抗剂：对豚鼠和大鼠5-羟色胺的细胞外水平的影响。

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The stimulation of terminal 5-HT(1B/1D) autoreceptors limits the effects of selective serotonin reuptake inhibitors on extracellular levels of 5-hydroxytryptamine (5-HT, serotonin) in vivo. Microdialysis studies show that acute oral administration of LY393558-a 5-HT reuptake inhibitor and antagonist at both the human 5-HT(1B) and 5-HT(1D) receptor-in the dose range 1-20 mg/kg, increases extracellular levels of 5-HT in both the guinea pig hypothalamus and rat frontal cortex. In both species, the levels of 5-HT that were attained were higher than following an acute, maximally effective dose of fluoxetine (20 mg/kg orally), reaching approximately 1500% in the guinea pig hypothalamus and 700% in the rat frontal cortex. In both species, the response to LY393558 (10 mg/kg p.o.) was impulse dependent, being absent in the presence of tetrodotoxin delivered at 1 microM via the microdialysis probe. The sensitivity to tetrodotoxin contrasted with the effects seen with DL-fenfluramine. Studies in rats showed that the microdialysate 5-HT concentration achieved in the frontal cortex after an acute challenge with LY393558 (5 mg/kg p.o.) was significantly greater than following a chronic regime of fluoxetine treatment (10 mg/kg/day orally for 21 days). Moreover, in rats chronically treated with LY393558 (5 mg/kg/day orally for 21 days), the mean basal concentration, 24 h after the final pretreatment dose, was of the same magnitude as that following chronic fluoxetine. However, in contrast to the response seen in fluoxetine-pretreated animals, a challenge dose of LY393558 still elicited a further increase in extracellular 5-HT in LY393558-pretreated animals. LY393558 is a potent 5-HT reuptake inhibitor and 5-HT(1B/1D) receptor antagonist. Microdialysis studies show that acute oral administration increases extracellular levels of 5-HT, by an impulse-dependent mechanism, above those produced by a maximally effective dose of fluoxetine, and in rats to levels only achieved following chronic fluoxetine treatment. Its neurochemical profile in vivo suggests that it may be a more effective antidepressant with the potential for producing an earlier onset of clinical activity than selective serotonin reuptake inhibitors.
机译：终端5-HT（1B / 1D）自身受体的刺激限制了选择性5-羟色胺再摄取抑制剂对体内5-羟色胺（5-HT，5-羟色胺）水平的影响。微透析研究表明，在人5-HT（1B）和5-HT（1D）受体上剂量为1-20 mg / kg的LY393558-5-HT再摄取抑制剂和拮抗剂急性口服给药会增加细胞外豚鼠下丘脑和大鼠额叶皮层中5-HT的水平。在这两个物种中，获得的5-HT水平均高于急性最大有效剂量氟西汀（口服20 mg / kg）后的水平，在豚鼠下丘脑中达到约1500％，在大鼠额叶皮层中达到700％ 。在这两个物种中，对LY393558（10 mg / kg p.o.）的反应都是脉冲依赖性的，在通过微透析探针以1 microM递送的河豚毒素存在下不存在。对河豚毒素的敏感性与DL-芬氟拉明所见的效果相反。对大鼠的研究表明，用LY393558（5 mg / kg po）急性攻击后，额叶皮层中达到的微透析液5-HT浓度显着高于长期接受氟西汀治疗（口服10 mg / kg /天21）后的浓度。天）。此外，在用LY393558（5 mg / kg /天，口服21天）进行慢性治疗的大鼠中，最终预处理剂量后24小时的平均基础浓度与慢性氟西汀治疗后的平均浓度相同。然而，与在氟西汀预处理的动物中看到的应答相反，LY393558的激发剂量仍引起在LY393558预处理的动物中细胞外5-HT的进一步增加。 LY393558是有效的5-HT再摄取抑制剂和5-HT（1B / 1D）受体拮抗剂。微透析研究表明，急性口服给药通过冲动依赖性机制使5-HT的细胞外水平增加，超过最大有效剂量的氟西汀产生的水平，并且在大鼠中达到慢性氟西汀治疗后达到的水平。它在体内的神经化学特征表明，它可能是一种比选择性5-羟色胺再摄取抑制剂更有效的抗抑郁药，具有产生更早发作的临床活性的潜力。

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