Routledge C, Hartley J, Gurling J, Ashworth-Preece M, Brown G, Dourish C T
Department of Neuropharmacology, Wyeth Research (U.K.) Ltd., Maidenhead, Berkshire.
Neuropharmacology. 1994 Mar-Apr;33(3-4):359-66. doi: 10.1016/0028-3908(94)90066-3.
SDZ 216,525 has been proposed to be a silent 5-HT1A receptor antagonist. The present study examined the potential intrinsic agonist action of SDZ 216,525 using two in vivo models of somatodendritic 5-HT1A autoreceptor function: 5-HT release using microdialysis and feeding behaviour of satiated animals. SDZ 216,525 (1 mg/kg s.c.) and the alpha 1-adrenoceptor antagonist prazosin (1 mg/kg s.c.) significantly decreased hippocampal 5-HT release. In addition, SDZ 216,525 (3 and 10 mg/kg s.c.) and prazosin (3 and 10 mg/kg s.c.) significantly increased food intake in satiated rats. The selective 5-HT1A receptor antagonist (RS)-WAY100135 (10 mg/kg s.c.) which has been demonstrated to block the effects of 8-OH-DPAT on 5-HT release and food intake had no significant effect on the response induced by SDZ 216,525. In contrast, the non-selective 5-HT1A receptor antagonist (-)-pindolol (8 mg/kg s.c.) attenuated both SDZ 216,525 responses. The decrease in hippocampal 5-HT release and increase in food intake induced by SDZ 216,525 suggest that the compound may be a 5-HT1A receptor partial agonist. However, the failure of the 5-HT1A receptor antagonist (RS)-WAY100135 to block the SDZ 216,525 responses suggests that SDZ 216,525 decreases 5-HT release and increases food intake by a mechanism other than 5-HT1A receptor agonism. The high affinity of SDZ 216,525 for the alpha 1-adrenoceptor, and the ability of prazosin to decrease 5-HT release and increase food intake, suggest that the effects of SDZ 216,525 may be mediated via an alpha 1-adrenoceptor antagonist action.
SDZ 216,525被认为是一种非活性的5-羟色胺1A（5-HT1A）受体拮抗剂。本研究使用两种树突状5-HT1A自身受体功能的体内模型，即利用微透析法检测5-羟色胺（5-HT）释放以及饱足动物的进食行为，来研究SDZ 216,525潜在的内在激动剂作用。SDZ 216,525（皮下注射1毫克/千克）和α1-肾上腺素能受体拮抗剂哌唑嗪（皮下注射1毫克/千克）显著降低了海马体中5-HT的释放。此外，SDZ 216,525（皮下注射3毫克/千克和10毫克/千克）和哌唑嗪（皮下注射3毫克/千克和10毫克/千克）显著增加了饱足大鼠的食物摄入量。已证实选择性5-HT1A受体拮抗剂（RS）-WAY100135（皮下注射10毫克/千克）可阻断8-羟基二丙胺基四氢萘（8-OH-DPAT）对5-HT释放和食物摄入量的影响，但对SDZ 216,525诱导的反应无显著影响。相反，非选择性5-HT1A受体拮抗剂（-）-吲哚洛尔（皮下注射8毫克/千克）减弱了SDZ 216,525的两种反应。SDZ 216,525引起的海马体中5-HT释放减少和食物摄入量增加表明，该化合物可能是一种5-HT1A受体部分激动剂。然而，5-HT1A受体拮抗剂（RS）-WAY100135未能阻断SDZ 216,525的反应，这表明SDZ 216,525通过5-HT1A受体激动作用以外的机制降低5-HT释放并增加食物摄入量。SDZ 216,525对α1-肾上腺素能受体具有高亲和力，且哌唑嗪具有降低5-HT释放和增加食物摄入量的能力，这表明SDZ 216,525的作用可能是通过α1-肾上腺素能受体拮抗剂作用介导的。
