Invernizzi R, Velasco C, Bramante M, Longo A, Samanin R
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Neuropharmacology. 1997 Apr-May;36(4-5):467-73. doi: 10.1016/s0028-3908(97)00060-9.
The aim of the present study was to compare the effects of citalopram, either alone or combined with 5-HT1A receptor antagonists, on extracellular serotonin levels in brain regions innervated by the dorsal or median raphe nuclei. Using intracerebral microdialysis in awake rats with separate probes in the frontal cortex or dorsal hippocampus, we studied the ability of 8 mg/kg s.c. (-)penbutolol, a beta-adrenoceptor antagonist with antagonist action at 5-HT1A and 5-HT1B receptors, and 0.3 mg/kg s.c. WAY-100635, a selective 5-HT1A receptor blocker, to modify the effect of 1 and 10 mg/kg i.p. citalopram on extracellular serotonin. Both doses of citalopram had more effect on extracellular serotonin levels in the dorsal hippocampus than in the frontal cortex. The effect of 1 mg/kg citalopram was significantly potentiated by (-)penbutolol in the frontal cortex only, but a clear-cut potentiation of the effect of citalopram was seen in both regions at a dose of 10 mg/kg. The effect of 10 mg/kg citalopram was potentiated by WAY-100635 in the frontal cortex but not in the dorsal hippocampus. In a second set of experiments, the combined effect of WAY-100635 and citalopram was studied in the same rat implanted with vertical probes in the striatum and dorsal hippocampus. Citalopram (1 and 10 mg/kg i.p.) raised extracellular serotonin to a similar extent in both regions. However, 0.3 mg/kg s.c. WAY-100635 potentiated the effect of 10 mg/kg citalopram in the striatum but not in the dorsal hippocampus. The results suggest that only a combined blockade of 5-HT1A and 5-HT1B receptors potentiates the effect of citalopram on extracellular concentrations of serotonin in the dorsal hippocampus. The findings may be relevant in designing clinical trials aimed at enhancing the antidepressant action of selective serotonin re-uptake inhibitors by combining them with serotonin receptor antagonists.
本研究的目的是比较西酞普兰单独使用或与5-HT1A受体拮抗剂联合使用时，对由中缝背核或中缝正中核支配的脑区细胞外5-羟色胺水平的影响。在清醒大鼠中使用脑内微透析技术，在额叶皮质或背侧海马体中分别插入探针，我们研究了8mg/kg皮下注射（-）喷布洛尔（一种对5-HT1A和5-HT1B受体具有拮抗作用的β-肾上腺素受体拮抗剂）和0.3mg/kg皮下注射WAY-100635（一种选择性5-HT1A受体阻滞剂）对1mg/kg和10mg/kg腹腔注射西酞普兰细胞外5-羟色胺作用的影响。两种剂量的西酞普兰对背侧海马体细胞外5-羟色胺水平的影响均大于额叶皮质。仅在额叶皮质中，（-）喷布洛尔显著增强了1mg/kg西酞普兰的作用，但在两个区域中，10mg/kg剂量的西酞普兰作用均有明显增强。10mg/kg西酞普兰的作用在额叶皮质中被WAY-100635增强，但在背侧海马体中未增强。在第二组实验中，在同一大鼠的纹状体和背侧海马体中植入垂直探针，研究WAY-100635和西酞普兰的联合作用。西酞普兰（1mg/kg和10mg/kg腹腔注射）在两个区域中使细胞外5-羟色胺升高的程度相似。然而，0.3mg/kg皮下注射WAY-100635增强了10mg/kg西酞普兰在纹状体中的作用，但在背侧海马体中未增强。结果表明，只有5-HT1A和5-HT1B受体的联合阻断才能增强西酞普兰对背侧海马体中5-羟色胺细胞外浓度的作用。这些发现可能与设计旨在通过将选择性5-羟色胺再摄取抑制剂与5-羟色胺受体拮抗剂联合使用来增强其抗抑郁作用的临床试验相关。
