Sprouse J, Braselton J, Reynolds L, Clarke T, Rollema H
Pfizer Global Research and Development, Groton, Connecticut 06340, USA.
Synapse. 2001 Jul;41(1):49-57. doi: 10.1002/syn.1059.
Systemic doses of fluoxetine slow dorsal raphe cell firing by blocking the reuptake carrier located in the cell body region with the surplus 5-HT thus generated activating inhibitory autoreceptors. The concurrent actions of fluoxetine on postsynaptic receptors in raphe projection areas has not been as thoroughly investigated, although it is presumed that a reduction in cell firing should curtail these targeted effects. The goal of the present studies was to assess the degree of postsynaptic receptor activation obtained with fluoxetine and relate it to cell body autoreceptor activation and the level of extracellular 5-HT obtained at the nerve endings. Changes in firing rates of CA3 hippocampal neurons following systemic administration of fluoxetine were used as a marker of SSRI-dependent changes in postsynaptic 5-HT receptor activation; monitoring of unit activity of neurons in the dorsal raphe nucleus served to gauge the degree of serotonergic input in a parallel series of animals. Estimates of the corresponding changes in terminal 5-HT release in the CA3 region were analyzed by microdialysis. The results indicate that fluoxetine inhibits hippocampal cell firing in a dose-dependent manner (ED(50) = 4.4 mg/kg i.v.) and one sensitive to pretreatment with the 5-HT(1A) antagonist WAY-100,635. Within the same dose range, increases in hippocampal extracellular 5-HT approaching 300% above basal levels were achieved. Both the changes in hippocampal neuronal activity and extracellular 5-HT are evident at doses of fluoxetine in excess of that required to inhibit dorsal raphe cell firing (ED(50) = 1.1 mg/kg i.v.). Taken together, these data suggest that increases in extracellular levels of 5-HT on the order of that observed are sufficient to alter postsynaptic excitability and that this accumulation of synaptic 5-HT and the subsequent activation of postsynaptic 5-HT(1A) receptors are achievable despite loss of firing-dependent 5-HT release.
全身性剂量的氟西汀通过阻断位于细胞体区域的再摄取载体来减缓中缝背核细胞的放电，由此产生的多余5-羟色胺（5-HT）会激活抑制性自身受体。尽管据推测细胞放电的减少应会减弱这些靶向效应，但氟西汀对中缝投射区域突触后受体的并发作用尚未得到充分研究。本研究的目的是评估氟西汀引起的突触后受体激活程度，并将其与细胞体自身受体激活以及神经末梢处细胞外5-HT水平相关联。全身性给予氟西汀后海马CA3神经元放电率的变化被用作突触后5-HT受体激活中依赖于选择性5-羟色胺再摄取抑制剂（SSRI）的变化的标志物；监测中缝背核神经元的单位活动用于衡量一系列平行动物中血清素能输入的程度。通过微透析分析CA3区域终末5-HT释放的相应变化估计值。结果表明，氟西汀以剂量依赖性方式抑制海马细胞放电（半数有效剂量（ED(50)）= 4.4毫克/千克静脉注射），且对用5-HT(1A)拮抗剂WAY-100,635预处理敏感。在相同剂量范围内，海马细胞外5-HT增加至比基础水平高出近300%。海马神经元活动和细胞外5-HT的变化在氟西汀剂量超过抑制中缝背核细胞放电所需剂量（ED(50) = 1.1毫克/千克静脉注射）时均很明显。综上所述，这些数据表明，所观察到的细胞外5-HT水平的升高足以改变突触后兴奋性，并且尽管依赖放电的5-HT释放减少，但这种突触5-HT的积累以及随后突触后5-HT(1A)受体的激活是可以实现 的。
