Mitchell S N, Greenslade R G, Cooper J
Eli Lilly and Company Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK.
Eur J Pharmacol. 2001 Nov 30;432(1):19-27. doi: 10.1016/s0014-2999(01)01469-8.
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.
终末5-羟色胺（5-HT）（1B/1D）自身受体的刺激作用可限制选择性5-羟色胺再摄取抑制剂对体内5-羟色胺（5-HT，血清素）细胞外水平的影响。微透析研究表明，急性口服LY393558（一种5-HT再摄取抑制剂，同时也是人5-HT（1B）和5-HT（1D）受体的拮抗剂），剂量范围为1-20mg/kg，可使豚鼠下丘脑和大鼠额叶皮质中的5-HT细胞外水平升高。在这两个物种中，所达到的5-HT水平均高于急性给予最大有效剂量氟西汀（20mg/kg口服）后的水平，在豚鼠下丘脑中达到约1500%，在大鼠额叶皮质中达到700%。在这两个物种中，对LY393558（10mg/kg口服）的反应均依赖冲动，当通过微透析探针给予1μM河豚毒素时则无此反应。对河豚毒素的敏感性与DL-芬氟拉明的作用形成对比。在大鼠中的研究表明，急性给予LY393558（5mg/kg口服）后额叶皮质中微透析液5-HT浓度显著高于慢性给予氟西汀治疗（10mg/kg/天口服21天）后的浓度。此外，在长期给予LY393558（5mg/kg/天口服21天）的大鼠中，末次预处理剂量后24小时的平均基础浓度与长期给予氟西汀后的浓度相当。然而，与氟西汀预处理动物的反应不同，给予LY393558激发剂量后，LY393558预处理动物的细胞外5-HT仍会进一步升高。LY393558是一种强效的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，急性口服可通过依赖冲动的机制使5-HT细胞外水平升高，高于最大有效剂量氟西汀所产生的水平，并且在大鼠中可达到仅在慢性给予氟西汀治疗后才达到的水平。其体内神经化学特征表明，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，具有更早产生临床活性的潜力。
