Fabre V, Beaufour C, Evrard A, Rioux A, Hanoun N, Lesch K P, Murphy D L, Lanfumey L, Hamon M, Martres M P
INSERM U288, Neuropsychopharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
Eur J Neurosci. 2000 Jul;12(7):2299-310. doi: 10.1046/j.1460-9568.2000.00126.x.
By taking up serotonin (5-hydroxytryptamine, 5-HT) released in the extracellular space, the 5-HT transporter (5-HTT) regulates central 5-HT neurotransmission. Possible adaptive changes in 5-HT neurotransmission in knock-out mice that do not express the 5-HT transporter were investigated with special focus on 5-HT1A and 5-HT1B receptors. Specific labelling with radioligands and antibodies, and competitive RT-PCR, showed that 5-HT1A receptor protein and mRNA levels were significantly decreased in the dorsal raphe nucleus (DRN), increased in the hippocampus and unchanged in other forebrain areas of 5-HTT-/- vs. 5-HTT+/+ mice. Such regional differences also concerned 5-HT1B receptors because a decrease in their density was found in the substantia nigra (-30%) but not the globus pallidus of mutant mice. Intermediate changes were noted in 5-HTT+/- mice compared with 5-HTT+/+ and 5-HTT-/- animals. Quantification of [35S]GTP-gamma-S binding evoked by potent 5-HT1 receptor agonists confirmed such changes as a decrease in this parameter was noted in the DRN (-66%) and the substantia nigra (-30%) but not other brain areas in 5-HTT-/- vs. 5-HTT+/+ mice. As expected from actions mediated by functional 5-HT1A and 5-HT1B autoreceptors, a decrease in brain 5-HT turnover rate after i.p. administration of ipsapirone (a 5-HT1A agonist), and an increased 5-HT outflow in the substantia nigra upon local application of GR 127935 (a 5-HT1B/1D antagonist) were observed in 5-HTT+/+ mice. Such effects were not detected in 5-HTT-/- mice, further confirming the occurrence of marked alterations of 5-HT1A and 5-HT1B autoreceptors in these animals.
5-羟色胺转运体（5-HTT）通过摄取细胞外空间释放的5-羟色胺（5-羟色胺，5-HT）来调节中枢5-HT神经传递。本研究以5-HT1A和5-HT1B受体为重点，对不表达5-HTT的基因敲除小鼠中5-HT神经传递可能的适应性变化进行了研究。用放射性配体和抗体进行特异性标记以及竞争性RT-PCR结果显示，与5-HTT+/+小鼠相比，5-HTT-/-小鼠中，背侧中缝核（DRN）的5-HT1A受体蛋白和mRNA水平显著降低，海马体中升高，其他前脑区域则无变化。这种区域差异也涉及5-HT1B受体，因为在突变小鼠的黑质中发现其密度降低了30%，而苍白球中未发现。与5-HTT+/+和5-HTT-/-动物相比，5-HTT+/-小鼠出现了中间变化。强效5-HT1受体激动剂诱发的[35S]GTP-γ-S结合定量结果证实了这些变化，因为在5-HTT-/-与5-HTT+/+小鼠中，DRN（-66%）和黑质（-30%）的该参数降低，而其他脑区未降低。正如功能性5-HT1A和5-HT1B自身受体介导的作用所预期的那样，在5-HTT+/+小鼠中，腹腔注射ipsapirone（一种5-HT1A激动剂）后，脑内5-HT周转率降低，局部应用GR 127935（一种5-HT1B/1D拮抗剂）后，黑质中5-HT流出增加。在5-HTT-/-小鼠中未检测到此类效应，进一步证实了这些动物中5-HT1A和5-HT1B自身受体发生了显著改变。
