Gobert A, Rivet J M, Cistarelli L, Millan M J
Psychopharmacology Department, Centre de Recherches de Croissy, Croissy-sur-Seine, France.
J Neurochem. 1997 Mar;68(3):1159-63. doi: 10.1046/j.1471-4159.1997.68031159.x.
In this study, we examined the influence of blockade of serotonin (5-HT)1A and/or 5-HT1B autoreceptors on the fluoxetine-induced increase in dialysate levels of 5-HT as compared with dopamine (DA) and noradrenaline (NAD) in single samples of the frontal cortex (FCx) of freely moving rats. Fluoxetine (10.0 mg/kg, s.c.) elicited a twofold increase in dialysate levels of 5-HT relative to baseline values. The selective 5-HT1A antagonist WAY 100,635 (0.16 mg/kg, s.c.) did not influence 5-HT release alone but doubled the influence of fluoxetine on basal levels. Similarly, the selective 5-HT 1B/1D antagonist GR 127,935 (2.5 mg/kg, s.c.) did not alter basal 5-HT levels alone and doubled the fluoxetine-induced increase in 5-HT levels. Combined administration of WAY 100,635 and GR 127,935 elicited an (at least) additive rise in the fluoxetine-induced increase in 5-HT levels to eightfold basal values, without modifying resting 5-HT levels. These changes were selective for 5-HT inasmuch as the parallel (twofold) increase in DA and NAD levels provoked by fluoxetine was not potentiated. The present data demonstrate that combined blockade of 5-HT1A and 5-HT1B autoreceptors markedly and selectively potentiates the fluoxetine-induced increase in dialysate levels of 5-HT versus DA and NAD in the FCx of freely moving rats. These observations suggest that 5-HT 1A/1B antagonism may represent a novel strategy for the improvement in the therapeutic profile of 5-HT reuptake inhibitor antidepressant agents and that 5-HT may be primarily involved in such interactions.
在本研究中，我们检测了5-羟色胺（5-HT）1A和/或5-HT1B自身受体的阻断对氟西汀诱导的5-HT透析液水平升高的影响，并与自由活动大鼠额叶皮质（FCx）单一样本中的多巴胺（DA）和去甲肾上腺素（NAD）进行比较。氟西汀（10.0毫克/千克，皮下注射）使5-HT透析液水平相对于基线值增加了两倍。选择性5-HT1A拮抗剂WAY 100,635（0.16毫克/千克，皮下注射）单独使用时不影响5-HT释放，但使氟西汀对基础水平的影响增加了一倍。同样，选择性5-HT 1B/1D拮抗剂GR 127,935（2.5毫克/千克，皮下注射）单独使用时不会改变基础5-HT水平，但使氟西汀诱导的5-HT水平升高增加了一倍。联合使用WAY 100,635和GR 127,935使氟西汀诱导的5-HT水平升高（至少）呈相加性增加至基础值的八倍，而不改变静息5-HT水平。这些变化对5-HT具有选择性，因为氟西汀引起的DA和NAD水平的平行（两倍）增加并未增强。目前的数据表明，联合阻断5-HT1A和5-HT1B自身受体可显著且选择性地增强氟西汀诱导的自由活动大鼠FCx中5-HT透析液水平相对于DA和NAD的升高。这些观察结果表明，5-HT 1A/1B拮抗作用可能代表了一种改善5-羟色胺再摄取抑制剂抗抑郁药治疗效果的新策略，并且5-HT可能主要参与了此类相互作用。
