5-羟色胺（5-HT）7型受体拮抗剂SB-269970对5-羟色胺能终末和细胞体释放5-羟色胺的影响。
The effect of SB-269970, a 5-HT(7) receptor antagonist, on 5-HT release from serotonergic terminals and cell bodies.
作者信息
Roberts C, Allen L, Langmead C J, Hagan J J, Middlemiss D N, Price G W
机构信息
Department of Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW.
出版信息
Br J Pharmacol. 2001 Apr;132(7):1574-80. doi: 10.1038/sj.bjp.0703979.
Abstract
- The presence of 5-HT(7) receptor mRNA and protein in 5-HT neurons suggests that this receptor may act as a 5-HT autoreceptor. In this study, the effect of the 5-HT(7) receptor antagonist, SB-269970 ((R)-1-[3-hydroxy phenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine), was investigated on 5-HT release in the guinea-pig and rat cortex and the rat dorsal raphe nucleus (DRN), using the techniques of in vitro [(3)H]-5-HT release or fast cyclic voltammetry, respectively. 2. Cortical slices were loaded with [(3)H]-5-HT and release was evoked by electrical stimulation. 5-CT inhibited the evoked release of [(3)H]-5-HT in a concentration-dependent manner. SB-269970 had no significant effect on [(3)H]-5-HT release while the 5-HT(1B) receptor antagonist, SB-224289 significantly potentiated [(3)H]-5-HT release. In addition, SB-269970 was unable to attenuate the 5-CT-induced inhibition of release while SB-224289 produced a rightward shift of the 5-CT response, generating estimated pK(B) values of 7.8 and 7.6 at the guinea-pig and rat terminal 5-HT autoreceptors respectively. 3. Rat DRN slices were electrically stimulated and the evoked 5-HT efflux detected by voltammetric analysis. 8-OH-DPAT inhibited evoked 5-HT efflux and was fully reversed by WAY 100635. SB-269970 had no effect on either 5-HT efflux per se or 8-OH-DPAT-induced inhibition of 5-HT efflux. In addition, 5-CT inhibited 5-HT efflux in a concentration-dependent manner. SB-269970 was unable to attenuate the 5-CT-induced inhibition of 5-HT efflux. 4. In conclusion, we were unable to provide evidence to suggest a 5-HT autoreceptor role for 5-HT(7) receptors. However, investigations with more selective 5-HT(7) receptor agonists are needed to confirm the data reported here.
摘要
- 5-羟色胺（5-HT）神经元中5-HT(7)受体信使核糖核酸（mRNA）和蛋白的存在表明，该受体可能作为一种5-HT自身受体发挥作用。在本研究中，使用体外[³H]-5-HT释放技术或快速循环伏安法，分别研究了5-HT(7)受体拮抗剂SB-269970（(R)-1-[3-羟基苯基）磺酰基]-2-[2-(4-甲基-1-哌啶基)乙基]吡咯烷）对豚鼠和大鼠皮层以及大鼠中缝背核（DRN）中5-HT释放的影响。2. 皮层切片用[³H]-5-HT加载，通过电刺激诱发释放。5-羧色胺（5-CT）以浓度依赖性方式抑制[³H]-5-HT的诱发释放。SB-269970对[³H]-5-HT释放无显著影响，而5-HT(1B)受体拮抗剂SB-224289显著增强[³H]-5-HT释放。此外，SB-269970无法减弱5-CT诱导的释放抑制，而SB-224289使5-CT反应向右移位，在豚鼠和大鼠终末5-HT自身受体处产生的估计解离常数（pK(B)）值分别为7.8和7.6。3. 对大鼠DRN切片进行电刺激，并通过伏安分析检测诱发的5-HT流出。8-羟基二丙胺基四氢萘（8-OH-DPAT）抑制诱发的5-HT流出，并被WAY 100635完全逆转。SB-269970对5-HT流出本身或8-OH-DPAT诱导的5-HT流出抑制均无影响。此外，5-CT以浓度依赖性方式抑制5-HT流出。SB-269970无法减弱5-CT诱导的5-HT流出抑制。4. 总之,我们无法提供证据表明5-HT(7)受体具有5-HT自身受体作用。然而，需要用更具选择性的5-HT(7)受体激动剂进行研究以证实此处报道的数据。
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