De Groote Lotte, Olivier Berend, Westenberg Herman G M
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
Eur J Pharmacol. 2003 Aug 22;476(1-2):71-7. doi: 10.1016/s0014-2999(03)02154-x.
To test the hypothesis that 5-HT1B receptors modulate serotonin (5-hydroxytryptamine, 5-HT) and dopamine release in the striatum, we used in vivo microdialysis in mice lacking 5-HT1B receptors. Local administration by reversed microdialysis of the selective 5-HT reuptake inhibitor, fluvoxamine (0.1-10 microM), concentration dependently increased 5-HT to the same extent in wildtype and in 5-HT1B knockout (KO) mice. Fluvoxamine (10 microM) increased dopamine levels similarly in both genotypes. The 5-HT releaser, fenfluramine (50 microM), increased both 5-HT and dopamine levels, but no difference was found between the genotypes. The 5-HT1B receptor agonist, 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one (CP-93,129), reduced 5-HT levels in the wildtype, but not in 5-HT1B KO mice. CP-93,129 at a concentration of 0.5 microM did not affect striatal dopamine outflow in either genotype, whereas dopamine outflow was increased 5-fold by 50 microM CP-93,129 in both genotypes. The CP-93,129-induced dopamine increase was not attenuated by ritanserin, a 5-HT2A/2C receptor antagonist, but was completely blocked by tetrodotoxin, demonstrating that the dopamine release was of neuronal origin. In conclusion, 5-HT1B autoreceptors are functionally present in the mouse striatum, but do not appear to play a significant role in the effects of a selective 5-HT reuptake inhibitor on extracellular 5-HT. In addition, the results in 5-HT1B knockout mice do not support a role of 5-HT1B heteroreceptors in the striatum on dopamine outflow in this brain area of mice.
为了验证5-羟色胺1B（5-HT1B）受体调节纹状体内5-羟色胺（5-羟色胺，5-HT）和多巴胺释放这一假说，我们在缺乏5-HT1B受体的小鼠中进行了体内微透析实验。通过反向微透析局部给予选择性5-HT再摄取抑制剂氟伏沙明（0.1 - 10微摩尔），在野生型和5-HT1B基因敲除（KO）小鼠中，5-HT浓度依赖性增加的程度相同。氟伏沙明（10微摩尔）在两种基因型中对多巴胺水平的增加作用相似。5-HT释放剂芬氟拉明（50微摩尔）可同时增加5-HT和多巴胺水平，但两种基因型之间未发现差异。5-HT1B受体激动剂1,4-二氢-3-(1,2,3,6-四氢-4-吡啶基)-5H-吡咯并[3,2-b]吡啶-5-酮（CP-93,129）可降低野生型小鼠的5-HT水平，但对5-HT1B基因敲除小鼠无此作用。浓度为0.5微摩尔的CP-93,129对两种基因型的纹状体多巴胺流出均无影响，而50微摩尔的CP-93,129可使两种基因型的多巴胺流出增加5倍。CP-93,129诱导的多巴胺增加未被5-HT2A/2C受体拮抗剂利坦色林减弱，但被河豚毒素完全阻断，表明多巴胺释放源于神经元。总之，5-HT1B自身受体在小鼠纹状体中具有功能，但在选择性5-HT再摄取抑制剂对细胞外5-HT的作用中似乎不起重要作用。此外，5-HT1B基因敲除小鼠的实验结果不支持5-HT1B异受体在小鼠该脑区纹状体多巴胺流出中发挥作用。
