Malagié I, Trillat A C, Bourin M, Jacquot C, Hen R, Gardier A M
Laboratoire de Neuropharmacologie UPRES EAD MENRT, Faculté de Pharmacie IFR-ISIT Institut de Signalisation et d'Innovation Thérapeutique, Université Paris-Sud, Châtenay-Malabry, France.
J Neurochem. 2001 Feb;76(3):865-71. doi: 10.1046/j.1471-4159.2001.00083.x.
We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 1B receptor subtype in mediating the effects of selective serotonin re-uptake inhibitors (SSRIs). Using in vivo intracerebral microdialysis in awake mice, we show that a single systemic administration of paroxetine (1 or 5 mg/kg, i.p.) increased extracellular serotonin levels [5-HT]ext in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, paroxetine at the two doses studied induced a larger increase in [5-HT]ext in knockout than in wild-type mice. In the frontal cortex, the effect of paroxetine was larger in mutants than in wild-type mice at the 1 mg/kg, but not at 5 mg/kg. In addition, either the absence of the 5-HT1B receptor or its blockade with the mixed 5-HT1B/1D receptor antagonist, GR 127935, potentiated the effect of a single administration of paroxetine on extracellular 5-HT levels more in the ventral hippocampus than in the frontal cortex. These data suggest that 5-HT1B autoreceptors limit the effects of SSRIs on dialysate 5-HT levels at serotonergic nerve terminals.
我们使用基因敲除小鼠和受体拮抗剂策略来研究5-羟色胺（5- HT）1B受体亚型在介导选择性5-羟色胺再摄取抑制剂（SSRI）作用中的贡献。通过对清醒小鼠进行体内脑微透析，我们发现单次腹腔注射帕罗西汀（1或5mg/kg）可提高野生型和突变型小鼠腹侧海马体和额叶皮质的细胞外5-羟色胺水平[5-HT]ext。然而，在腹侧海马体中，研究的两种剂量的帕罗西汀在基因敲除小鼠中诱导的[5-HT]ext升高幅度大于野生型小鼠。在额叶皮质中，1mg/kg剂量的帕罗西汀对突变型小鼠的作用大于野生型小鼠，但5mg/kg时并非如此。此外，5-HT1B受体缺失或用5-HT1B/1D受体混合拮抗剂GR 127935阻断该受体，相比于额叶皮质，在腹侧海马体中对单次给予帕罗西汀后细胞外5-羟色胺水平的增强作用更大。这些数据表明，5-HT1B自身受体限制了SSRI对5-羟色胺能神经末梢透析液中5-羟色胺水平的影响。
