De Groote Lotte, Olivier Berend, Westenberg Herman G M
Department of Psychiatry, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
Eur J Pharmacol. 2002 Mar 29;439(1-3):93-100. doi: 10.1016/s0014-2999(02)01417-6.
The effects of two selective serotonin reuptake inhibitors on 5-hydroxy-tryptamine (5-HT) in the hippocampus were studied in wildtype and in 5-HT(1B) receptor knockout mice using in vivo microdialysis. Basal 5-HT levels in the hippocampus were not different between the two genotypes. The functional absence of 5-HT(1B) receptors was examined in the knockout mice by local infusion of the 5-HT(1B) receptor agonist, 1,4-Dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one (CP93129) into the hippocampus. CP93129 (1 microM) decreased 5-HT levels in wildtype mice, but not in 5-HT(1B) knockout mice. Systemic administration of the selective 5-HT reuptake inhibitor paroxetine (5 mg/kg, i.p.) increased extracellular 5-HT levels. The increase of 5-HT in 5-HT(1B) knockout mice was almost twofold higher than in wildtype mice. Systemic administration of selective 5-HT reuptake inhibitors stimulates both terminal 5-HT(1B) autoreceptors and somatodendritic 5-HT(1A) autoreceptors. Therefore, the selective 5-HT reuptake inhibitor, fluvoxamine, was applied locally into the hippocampus to investigate the role of the terminal 5-HT(1B) autoreceptors. Local administration of 0.3 microM fluvoxamine resulted in comparable increases in extracellular 5-HT in both genotypes, whereas 1.0 microM fluvoxamine produced a twofold greater increase in 5-HT levels in 5-HT(1B) knockout as compared to wildtype mice. In conclusion, the differences in hippocampal 5-HT output between wildtype and 5-HT(1B) knockout mice after local or systemic administration of selective 5-HT reuptake inhibitors show that 5-HT(1B) autoreceptors play a significant role in the inhibition of 5-HT release at serotonergic nerve terminals. In addition, the different dose-response to fluvoxamine suggests that 5-HT(1B) knockout mice have possible adaptations of 5-HT transporters in order to compensate for the loss of the terminal 5-HT(1B) autoreceptor.
利用体内微透析技术，在野生型和5-羟色胺（5-HT）1B受体基因敲除小鼠中研究了两种选择性5-羟色胺再摄取抑制剂对海马体中5-羟色胺（5-HT）的影响。两种基因型小鼠海马体中的基础5-HT水平并无差异。通过向5-HT1B受体基因敲除小鼠海马体局部注射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（CP93129），检测了5-HT1B受体的功能缺失情况。CP93129（1微摩尔）可降低野生型小鼠的5-HT水平，但对5-HT1B受体基因敲除小鼠无此作用。选择性5-羟色胺再摄取抑制剂帕罗西汀（5毫克/千克，腹腔注射）全身给药可提高细胞外5-HT水平。5-HT1B受体基因敲除小鼠中5-HT的增加量几乎是野生型小鼠的两倍。选择性5-羟色胺再摄取抑制剂全身给药可刺激终末5-HT1B自身受体和树突-胞体5-HT1A自身受体。因此，将选择性5-羟色胺再摄取抑制剂氟伏沙明局部注入海马体，以研究终末5-HT1B自身受体的作用。局部注射0.3微摩尔氟伏沙明后，两种基因型小鼠细胞外5-HT的增加量相当，而注射1.0微摩尔氟伏沙明后，5-HT1B受体基因敲除小鼠的5-HT水平增加量是野生型小鼠的两倍。总之，局部或全身给予选择性5-羟色胺再摄取抑制剂后，野生型和5-HT1B受体基因敲除小鼠海马体中5-HT输出的差异表明，5-HT1B自身受体在抑制5-羟色胺能神经终末的5-HT释放中起重要作用。此外，对氟伏沙明不同的剂量反应表明，5-HT1B受体基因敲除小鼠的5-羟色胺转运体可能发生了适应性变化，以补偿终末5-HT1B自身受体的缺失。
