Beck S G, Birnstiel S, Choi K C, Pouliot W A
Department of Pharmacology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois 60153, USA.
J Pharmacol Exp Ther. 1997 Apr;281(1):115-22.
Fluoxetine is a 5-hydroxytryptamine (5-HT, serotonin)-selective reuptake inhibitor (SSRI) and is one of the main drugs used for the treatment of depression. Because it takes 2 to 3 weeks of treatment before clinical efficacy is manifest, the acute actions of fluoxetine cannot account for the clinical actions of the drug. The chronic effects of fluoxetine have not been completely delineated. The experiments detailed here investigate the chronic effects of fluoxetine on 5-HT and gamma-aminobutyric acid (GABA) receptor-mediated actions using intracellular recording techniques in hippocampal brain slices. Rats were treated with fluoxetine for 3 weeks via osmotic minipumps implanted s.c. Fluoxetine and norfluoxetine plasma levels were determined. The hippocampal pyramidal cell characteristics and the 5-HT1A and GABA(B) receptor-mediated hyperpolarization were measured in the CA1 and the CA3 subfields. The 5-HT4 receptor-mediated decrease in the slow afterhyperpolarization amplitude was also recorded in area CA1. The time constant, magnitude of the change in resistance during 300-ms hyperpolarizing current pulses and half-decay time of the sAHP were altered by chronic fluoxetine treatment in area CA1 pyramidal cells. No changes were seen in any of the active or passive membrane properties of the CA3 hippocampal pyramidal cells. Fluoxetine treatment increased the potency of 5-HT for the 5-HT1A receptor-mediated hyperpolarization in area CA1, but not area CA3, and decreased the potency of baclofen for the GABA(B) receptor-mediated hyperpolarization in area CA1, but not area CA3. The characteristics of the concentration-response curve for the 5-HT-mediated decrease in sAHP amplitude in area CA1 were not altered by fluoxetine treatment. Chronic fluoxetine selectively and differentially altered the cell characteristics and the 5-HT1A and GABA(B) receptor-mediated responses in area CA1 of the hippocampus, which forms the final common output of the hippocampus.
氟西汀是一种5-羟色胺（5-HT，血清素）选择性再摄取抑制剂（SSRI），是治疗抑郁症的主要药物之一。由于临床疗效在治疗2至3周后才会显现，因此氟西汀的急性作用无法解释该药物的临床作用。氟西汀的慢性作用尚未完全阐明。此处详述的实验利用海马脑片的细胞内记录技术，研究氟西汀对5-HT和γ-氨基丁酸（GABA）受体介导作用的慢性影响。通过皮下植入渗透微型泵，对大鼠进行3周的氟西汀治疗。测定氟西汀和去甲氟西汀的血浆水平。在CA1和CA3亚区测量海马锥体细胞特征以及5-HT1A和GABA(B)受体介导的超极化。在CA1区也记录了5-HT4受体介导的慢后超极化幅度降低。慢性氟西汀治疗改变了CA1区锥体细胞的时间常数、300毫秒超极化电流脉冲期间电阻变化的幅度以及sAHP的半衰期。海马CA3锥体细胞的任何主动或被动膜特性均未观察到变化。氟西汀治疗增加了5-HT对CA1区5-HT1A受体介导超极化的效力，但对CA3区无效，并且降低了巴氯芬对CA1区GABA(B)受体介导超极化的效力，但对CA3区无效。氟西汀治疗未改变CA1区5-HT介导的sAHP幅度降低的浓度-反应曲线特征。慢性氟西汀选择性且差异性地改变了海马CA1区的细胞特征以及5-HT1A和GABA(B)受体介导的反应，而CA1区是海马的最终共同输出区域。
