Dupuis D S, Pauwels P J, Radu D, Hall H
Cellular and Molecular Biology Department, Centre de Recherche Pierre Fabre, Castres, France.
Eur J Neurosci. 1999 May;11(5):1809-17. doi: 10.1046/j.1460-9568.1999.00600.x.
G-protein activation mediated by serotonin 5-HT1A receptors in human and monkey brain was investigated by using quantitative autoradiography of agonist-stimulated [35S]GTPgammaS binding to whole-hemisphere brain sections. [35S]GTPgammaS binding was stimulated by the mixed 5-HT1A/1B/1D agonist L 694247 (10 microm) in human brain regions enriched in 5-HT1A binding sites [e.g. hippocampus (132-137%), superficial layers of the neocortex (37-61%), and cingulate and entorhinal cortex (34 and 32%, respectively)]. L 694247 caused virtually no stimulation in regions with 5-HT1B/1D receptors, such as substantia nigra, caudate nucleus and putamen. Similar results were obtained with monkey brain sections. The L 694247-mediated [35S]GTPgammaS-binding responses in human and monkey brain sections were antagonized by the selective, silent 5-HT1A antagonist WAY 100635 (10 microm). The 5-HT1B inverse agonist SB 224289 (10 microm) did not affect the [35S]GTPgammaS-binding response of L 694247. The distribution pattern of the [35S]GTPgammaS-binding response and the antagonist profile suggest the L 694247-induced response in human and monkey brain is mediated by 5-HT1A receptors. A weak stimulation of [35S]GTPgammaS binding was also observed in human hippocampus with either 10 microm 8-OH-DPAT (25 +/- 4%) or naratriptan (42 +/- 2%) compared with that obtained with L 694247. In conclusion, G-protein activation by 5-HT1A receptors can be measured in human and monkey brain sections. L 694247 appears to possess higher efficacy at 5-HT1A receptors compared with 8-OH-DPAT and naratriptan.
通过对激动剂刺激的[35S]GTPγS与全脑半球脑切片结合进行定量放射自显影，研究了5-羟色胺5-HT1A受体介导的人和猴脑中G蛋白激活情况。在富含5-HT1A结合位点的人脑区域（如海马体（132 - 137%）、新皮质浅层（37 - 61%）以及扣带回和内嗅皮质（分别为34%和32%）），混合的5-HT1A/1B/1D激动剂L 694247（10微摩尔）可刺激[35S]GTPγS结合。L 694247在具有5-HT1B/1D受体的区域（如黑质、尾状核和壳核）几乎不产生刺激作用。猴脑切片也得到了类似结果。人和猴脑切片中L 694247介导的[35S]GTPγS结合反应被选择性、无活性的5-HT1A拮抗剂WAY 100635（10微摩尔）拮抗。5-HT1B反向激动剂SB 224289（10微摩尔）不影响L 694247的[35S]GTPγS结合反应。[35S]GTPγS结合反应的分布模式和拮抗剂特征表明，人和猴脑中L 694247诱导的反应是由5-HT1A受体介导的。与L 694247相比，在人脑海马体中，10微摩尔的8-OH-DPAT（25±4%）或那拉曲普坦（42±2%）也观察到对[35S]GTPγS结合的微弱刺激。总之，在人和猴脑切片中可以检测到5-HT1A受体介导的G蛋白激活。与8-OH-DPAT和那拉曲普坦相比，L 694247在5-HT1A受体上似乎具有更高的效力。
