Koe B K, Lebel L A
Central Research Division, Pfizer Inc., Groton, CT 06340, USA.
Arch Int Pharmacodyn Ther. 1995 Mar-Apr;329(2):231-44.
The results of the present study show that the down-regulation of beta-adrenoceptors of rat brain, induced by subacute administration of sertraline, is facilitated when this selective serotonin reuptake inhibitor was co-administered with the serotonin releaser, norfenfluramine, or the serotonin terminal autoreceptor antagonist, methiothepin. The respective drug combination produced a reduction in Bmax of [3H]dihydroalprenolol binding to cortical membranes of treated rats at a dose of the releaser, release enhancer, or sertraline, which was ineffective when administered alone. In a similar manner, the 5-HT1A agonists, gepirone and 8-OH-DPAT, were found to facilitate the downregulation of beta-adrenoceptors induced by sertraline. The 5-HT1B agonist, 3-trifluoromethylphenylpiperazine, and the 5-HT2 antagonist, ritanserin, showed neither facilitation nor antagonism of sertraline, but the 5-HT3 antagonist, ondansetron, attenuated the decrease of Bmax of [3H]dihydroalprenolol binding elicited by sertraline. Agents that putatively increase the serotoninergic activity facilitated the down-regulation of beta-adrenoceptors induced by sertraline, suggesting that the enhancement of serotonin transmission, expected of the selective serotonin reuptake inhibitor itself, may play a role in this effect of sertraline. Whether the downregulation of brain beta-adrenoceptors by sertraline plays any role in its antidepressant activity cannot be deduced from these experiments.
本研究结果表明，当选择性5-羟色胺再摄取抑制剂舍曲林与5-羟色胺释放剂去甲氟西汀或5-羟色胺终末自身受体拮抗剂甲硫噻平联合使用时，亚急性给予舍曲林所诱导的大鼠脑β-肾上腺素能受体下调会加速。各自的药物组合在释放剂、释放增强剂或舍曲林的剂量下，使[3H]二氢阿普洛尔与处理大鼠皮质膜结合的Bmax降低，单独给药时则无效。同样，5-HT1A激动剂吉哌隆和8-OH-DPAT被发现可加速舍曲林诱导的β-肾上腺素能受体下调。5-HT1B激动剂3-三氟甲基苯基哌嗪和5-HT2拮抗剂利坦色林对舍曲林既无促进作用也无拮抗作用，但5-HT3拮抗剂昂丹司琼减弱了舍曲林引起的[3H]二氢阿普洛尔结合Bmax的降低。推测增加5-羟色胺能活性的药物促进了舍曲林诱导的β-肾上腺素能受体下调，这表明选择性5-羟色胺再摄取抑制剂本身预期的5-羟色胺传递增强可能在舍曲林的这一作用中发挥作用。从这些实验中无法推断出舍曲林对脑β-肾上腺素能受体的下调在其抗抑郁活性中是否起任何作用。
