O'Neill M F, Dobson D R, Sanger G J
Lilly Research Centre, Erl Wood Manor, Sunninghill Road, Windlesham, GU20 6PH, Surrey, UK.
Eur J Pharmacol. 2000 Jun 30;399(1):49-55. doi: 10.1016/s0014-2999(00)00345-9.
Previous studies in guinea pigs have shown that while a serotonin 5-HT(1B/D) receptor agonist, GR46611, does not induce locomotor activation when given alone, it markedly enhances the locomotor response to selective 5-HT(1A) receptor agonists, 8-OH-DPAT and buspirone. In these studies, we found that another 5-HT(1B/D) agonist, 3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate (SKF99101H), significantly elevated locomotor activity in guinea pigs when given alone. We assessed the relative contribution of 5-HT1(1A) and 5-HT(1B/D) receptors in the mediation of this effect. Activity was measured by photobeam interrupts in opaque Perspex cylinders linked to a computer. SKF99101H (20 mg/kg s. c.) significantly increased the locomotor activity in guinea pigs. The locomotor stimulant effect of SKF99101H (20 mg/kg s.c) was reversed by the selective 5-HT(1B/D) receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl -1,2,4-oxadiazol-3-yl)[1,1biphenyl]4-carboxamide (GR127935; 0.06-0. 25 mg/kg s.c.). The 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY100635; 0.05-0.25 mg/kg s.c.), slightly but significantly attenuated the hyperactivity induced by SKF99101H. These findings suggest that 5-HT(1B/D) receptor agonists may require concomitant activation of 5-HT(1A) receptors to induce locomotor activity in guinea pigs. The 5-HT(2A) receptor antagonist 6[2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]-ethyl]-7-methyl- 5H-thiazol[3,2-a]pyrimidin-5-one (ritanserin) had no effect on SKF99101H-induced hyperactivity, suggesting that these receptors are not involved in the mediation of SKF99101H-induced hyperactivity. SKF99101H-induced hyperactivity was significantly attenuated by the D(1) dopamine receptor antagonist SCH 23390 (0.005-025 mg/kg), but not by the D(2) dopamine receptor antagonist raclopride (0.25-1.0 mg/kg), possibly suggesting the selective involvement of D(1) dopaminergic receptors in the mediation of the stimulant actions of the 5-HT(1B/D) agonist.
先前在豚鼠身上进行的研究表明，血清素5-HT(1B/D)受体激动剂GR46611单独给药时不会诱发运动激活，但它能显著增强对选择性5-HT(1A)受体激动剂8-OH-DPAT和丁螺环酮的运动反应。在这些研究中，我们发现另一种5-HT(1B/D)激动剂3-(2-二甲基氨基乙基)-4-氯-5-丙氧基吲哚半富马酸盐（SKF99101H）单独给药时能显著提高豚鼠的运动活性。我们评估了5-HT1(1A)和5-HT(1B/D)受体在介导这种效应中的相对作用。通过与计算机相连的不透明有机玻璃圆筒中的光束中断来测量活动。SKF99101H（20毫克/千克皮下注射）显著增加了豚鼠的运动活性。选择性5-HT(1B/D)受体拮抗剂N-[4-甲氧基-3-(4-甲基-1-哌嗪基)phenyl]-2'-甲基-4'-(5-甲基-1,2,4-恶二唑-3-基)[1,1-联苯]4-甲酰胺（GR127935；0.06 - 0.25毫克/千克皮下注射）可逆转SKF99101H（20毫克/千克皮下注射）的运动刺激作用。5-HT(1A)受体拮抗剂N-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-N-(2-吡啶基)环己烷甲酰胺三盐酸盐（WAY100635；0.05 - 0.25毫克/千克皮下注射）轻微但显著减弱了SKF99101H诱导的多动。这些发现表明，5-HT(1B/D)受体激动剂可能需要同时激活5-HT(1A)受体才能在豚鼠中诱发运动活性。5-HT(2A)受体拮抗剂6[2-[4-[双(4-氟苯基)亚甲基]-1-哌啶基]-乙基]-7-甲基-5H-噻唑并[3,2-a]嘧啶-5-酮（利坦色林）对SKF99101H诱导的多动没有影响，表明这些受体不参与介导SKF99101H诱导的多动。D(1)多巴胺受体拮抗剂SCH 23390（0.005 - 0.25毫克/千克）显著减弱了SKF99101H诱导的多动，但D(2)多巴胺受体拮抗剂雷氯必利（0.25 - 1.0毫克/千克）没有，这可能表明D(1)多巴胺能受体选择性地参与了5-HT(1B/D)激动剂刺激作用的介导。
