Newman-Tancredi A, Rivet J-M, Cussac D, Touzard M, Chaput C, Marini L, Millan M J
Dept. of Psychopharmacology, Institut de Recherches Servier, 125 Chemin de Ronde, 78290, Croissy-sur-Seine, France.
Naunyn Schmiedebergs Arch Pharmacol. 2003 Sep;368(3):188-99. doi: 10.1007/s00210-003-0788-2. Epub 2003 Aug 16.
This study employed [(35)S]guanosine 5'- O-(3-thiotriphosphate) ([(35)S]GTPgammaS) binding to compare the actions of antipsychotic agents known to stimulate cloned, human 5-HT(1A) receptors with those of reference agonists at postsynaptic 5-HT(1A) receptors. In rat hippocampal membranes, the following order of efficacy was observed (maximum efficacy, E(max), values relative to 5-HT=100): (+)8-OH-DPAT (85), flesinoxan (62), eltoprazine (60), S14506 (59), S16924 (48), buspirone (41), S15535 (22), clozapine (22), ziprasidone (21), pindolol (7), p-MPPI (0), WAY100,635 (0), spiperone (0). Despite differences in species and tissue source, the efficacy and potency (pEC(50)) of agonists (with the exception of clozapine) correlated well with those determined previously at human 5-HT(1A) receptors expressed in Chinese hamster ovary (CHO) cells. In contrast, clozapine was more potent at hippocampal membranes. The selective antagonists p-MPPI and WAY100,635 abolished stimulation of binding by (+)8-OH-DPAT, clozapine and S16924 (p-MPPI), indicating that these actions were mediated specifically by 5-HT(1A) receptors. Clozapine and S16924 also attenuated 5-HT- and (+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding, consistent with partial agonist properties. In [(35)S]GTPgammaS autoradiographic studies, 5-HT-induced stimulation, mediated through 5-HT(1A) receptors, was more potent in the septum (pEC(50) approximately 6.5) than in the dentate gyrus of the hippocampus (pEC(50) approximately 5) suggesting potential differences in coupling efficiency or G protein expression. Though clozapine (30 and 100 microM) did not enhance [(35)S]GTPgammaS labelling in any structure, S16924 (10 micro M) modestly increased [(35)S]GTPgammaS labelling in the dentate gyrus. On the other hand, both these antipsychotic agents attenuated 5-HT (10 microM)-stimulated [(35)S]GTPgammaS binding in the dentate gyrus and septum. In conclusion, clozapine, S16924 and ziprasidone act as partial agonists for G protein activation at postsynaptic 5-HT(1A) receptors in the hippocampus. These data support a role of postsynaptic 5-HT(1A) receptors in the functional profiles of certain antipsychotic agents.
本研究采用[（35）S]鸟苷5'-O-（3-硫代三磷酸）（[（35）S]GTPγS）结合法，比较已知能刺激克隆的人5-HT（1A）受体的抗精神病药物与参考激动剂对突触后5-HT（1A）受体的作用。在大鼠海马膜中，观察到以下效力顺序（相对于5-HT = 100的最大效力E（max）值）：（+）8-OH-DPAT（85）、氟辛克生（62）、依托必利（60）、S14506（59）、S16924（48）、丁螺环酮（41）、S15535（22）、氯氮平（22）、齐拉西酮（21）、吲哚洛尔（7）、p-MPPI（0）、WAY100,635（0）、螺哌隆（0）。尽管物种和组织来源存在差异，但激动剂（氯氮平除外）的效力和效价（pEC（50））与先前在中华仓鼠卵巢（CHO）细胞中表达的人5-HT（1A）受体所测定的结果相关性良好。相比之下，氯氮平在海马膜上的效力更强。选择性拮抗剂p-MPPI和WAY100,635消除了（+）8-OH-DPAT、氯氮平和S16924（p-MPPI）对结合的刺激作用，表明这些作用是由5-HT（1A）受体特异性介导的。氯氮平和S16924也减弱了5-HT和（+）8-OH-DPAT刺激的[（35）S]GTPγS结合，这与部分激动剂特性一致。在[（35）S]GTPγS放射自显影研究中，通过5-HT（1A）受体介导的5-HT诱导的刺激在隔区（pEC（50）约为6.5）比在海马齿状回（pEC（50）约为5）更强，这表明在偶联效率或G蛋白表达方面可能存在差异。尽管氯氮平（30和100μM）在任何结构中均未增强[（35）S]GTPγS标记，但S16924（10μM）适度增加了齿状回中的[（35）S]GTPγS标记。另一方面，这两种抗精神病药物均减弱了齿状回和隔区中5-HT（10μM）刺激的[（35）S]GTPγS结合。总之，氯氮平、S16924和齐拉西酮在海马突触后5-HT（1A）受体处作为G蛋白激活的部分激动剂发挥作用。这些数据支持突触后5-HT（1A）受体在某些抗精神病药物功能谱中的作用。
