Dawson L A, Nguyen H Q
CNS Disorders Division, Wyeth-Ayerst Research, Princeton, NJ 08543-8000, USA.
Eur J Pharmacol. 1998 Mar 12;345(1):41-6. doi: 10.1016/s0014-2999(97)01580-x.
Clinical studies in which serotonin specific reuptake inhibitors have been co-administered with pindolol have demonstrated a shortened time to onset of antidepressant activity. This effect has been attributed to the antagonist effects of pindolol at the presynaptic 5-HT1A receptor which augments the action of the serotonin specific reuptake inhibitors. In the present study, we demonstrate that acute fluoxetine-induced increases in extracellular serotonin concentrations, as measured by microdialysis in the frontal cortex, can be potentiated by 5-HT1A receptor blockade using N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexa necarboxamide (WAY100635), the silent and selective 5-HT1A receptor antagonist. WAY100635 at doses as low as 0.03 mg/kg s.c. maintained this potentiation effect across a range of fluoxetine doses. In addition, using antagonists with different intrinsic agonist activities for the 5-HT1A receptor, we have determined that only compounds with very low intrinsic agonist activity can produce a potentiation of the acute fluoxetine-induced increases in extracellular serotonin.
在血清素特异性再摄取抑制剂与吲哚洛尔联合给药的临床研究中，已证明抗抑郁活性起效时间缩短。这种效应归因于吲哚洛尔对突触前5-HT1A受体的拮抗作用，该作用增强了血清素特异性再摄取抑制剂的作用。在本研究中，我们证明，使用N-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-N-(吡啶基)环己烷甲酰胺（WAY100635，一种沉默且选择性的5-HT1A受体拮抗剂）阻断5-HT1A受体，可增强急性氟西汀诱导的额叶皮质细胞外血清素浓度升高，这是通过微透析测量得出的。WAY100635皮下注射低至0.03 mg/kg的剂量，在一系列氟西汀剂量范围内均能维持这种增强效应。此外，使用对5-HT1A受体具有不同内在激动剂活性的拮抗剂，我们已确定只有内在激动剂活性非常低的化合物才能增强急性氟西汀诱导的细胞外血清素升高。
