Marek G J, Aghajanian G K
Department of Psychiatry, Yale University School of Medicine, Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven 06508.
Eur J Pharmacol. 1994 Jul 1;259(2):137-41. doi: 10.1016/0014-2999(94)90502-9.
Electrophysiological studies have suggested that a subpopulation of interneurons near the border of layer II and III in rat piriform cortex are excited by serotonin (5-hydroxytryptamine; 5-HT) via 5-HT2A (formerly 5-HT2) rather than 5-HT2C (formerly 5-HT1C) receptors. However, the pharmacological agents used in those studies were limited in specificity. In the present study, we tested a new, highly selective 5-HT2A receptor antagonist MDL 100,907 (R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl-ethyl)]-4- piperidine-methanol, which has a 300-fold greater affinity for 5-HT2A than 5-HT1C receptors or alpha 1-adrenoceptors) on excitatory responses of interneurons to 5-HT in rat piriform cortex slices. We observed a parallel, reversible rightward shift in the 5-HT concentration-response curve in the presence of 1-10 nM concentrations of MDL 100,907. Schild regression analysis resulted in a slope of 1.13 and a Kd value of 1.17 which is close to the published Ki value of 0.36 for MDL 100,907. These data confirm that 5-HT2A rather than 5-HT2C receptors mediate excitation by 5-HT of interneurons in the piriform cortex. Because of its rapid equilibration and reversibility, MDL 100,907 appears to be an excellent tool for studies of 5-HT2A receptor function in the brain.
电生理研究表明，大鼠梨状皮质II层和III层边界附近的一部分中间神经元可被血清素（5-羟色胺；5-HT）通过5-HT2A（以前称为5-HT2）而非5-HT2C（以前称为5-HT1C）受体兴奋。然而，这些研究中使用的药理剂在特异性方面存在局限性。在本研究中，我们测试了一种新型、高选择性的5-HT2A受体拮抗剂MDL 100,907（R-(+)-α-(2,3-二甲氧基苯基)-1-[2-(4-氟苯基-乙基)]-4-哌啶甲醇，其对5-HT2A的亲和力比对5-HT1C受体或α1-肾上腺素能受体高300倍）对大鼠梨状皮质切片中中间神经元对5-HT的兴奋性反应的影响。我们观察到，在存在1-10 nM浓度的MDL 100,907时，5-HT浓度-反应曲线出现平行、可逆的右移。Schild回归分析得出斜率为1.13，Kd值为1.17，这与已发表的MDL 100,907的Ki值0.36接近。这些数据证实，在梨状皮质中，是5-HT2A而非5-HT2C受体介导了5-HT对中间神经元的兴奋作用。由于其快速平衡和可逆性，MDL 100,907似乎是研究大脑中5-HT2A受体功能的极佳工具。
