Twist E C, Brammer M J, Stephenson J D, Corn T H, Campbell I C
Department of Neuroscience, Institute of Psychiatry, London, U.K.
Biochem Pharmacol. 1990 Nov 1;40(9):2111-6. doi: 10.1016/0006-2952(90)90242-d.
We have previously shown that chronic administration of the 5-hydroxytryptamine (5-HT) receptor antagonist, ritanserin (10 mg/kg/day) or the monoamine oxidase type A inhibitor (MAOI), clorgyline (2 mg/kg/day), results in a reduction in 5-HT2 receptor number in rat cerebral cortex. This study investigates the effects of acute and chronic ritanserin administration, on 5-HT2 receptor linked inositol phospholipid hydrolysis in rat cortical slices and compares it with the effect of a chronic clorgyline regimen. [3H]Myo-inositol (50 microCi) was used to label inositol phospholipids. Their subsequent hydrolysis in the presence or absence of 5-HT was determined by the accumulation of [3H]myoinositol monophosphate ([3H]InsP). Addition of 5 nM ritanserin to slices had no effect on basal or 5-HT stimulated [3H]InsP accumulation whereas 100 nM ritanserin blocked the stimulated response by 65%. Acutely, ritanserin (15 mg/kg i.p.) completely blocked 5-HT stimulated [3H]InsP accumulation. Chronic ritanserin or clorgyline treatment had no effect on basal levels of [3H]InsP accumulation compared to controls (mean value 3125 +/- 298 dpm/mg protein). Ritanserin increased 5-HT stimulated [3H]InsP accumulation at 1 microM, 100 microM and 1 mM 5-HT and this effect was significant at 100 microM 5-HT. Clorgyline had no significant or consistent effect on 5-HT stimulated [3H]InsP accumulation at 1 microM, 100 microM and 1 mM 5-HT. Thus the effects of both chronic clorgyline and ritanserin administration on 5-HT2 linked inositol phospholipid hydrolysis do not correlate with their effects on 5-HT2 receptor number (Bmax). The situation is further complicated since ritanserin significantly increases phosphatidylinositol (PtdIns), phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) labelling whereas clorgyline significantly increases PtdIns and PtdIns4P labelling. The implications of this are discussed.
我们之前已经表明，长期给予5-羟色胺（5-HT）受体拮抗剂利坦色林（10毫克/千克/天）或A型单胺氧化酶抑制剂（MAOI）氯吉兰（2毫克/千克/天），会导致大鼠大脑皮层中5-HT2受体数量减少。本研究调查了急性和长期给予利坦色林对大鼠皮层切片中与5-HT2受体相关的肌醇磷脂水解的影响，并将其与长期给予氯吉兰方案的效果进行比较。[3H]肌醇（50微居里）用于标记肌醇磷脂。通过[3H]肌醇单磷酸（[3H]InsP）的积累来测定它们在有无5-HT存在时的后续水解情况。向切片中添加5纳摩尔利坦色林对基础或5-HT刺激的[3H]InsP积累没有影响，而100纳摩尔利坦色林可使刺激反应阻断65%。急性给予利坦色林（15毫克/千克腹腔注射）可完全阻断5-HT刺激的[3H]InsP积累。与对照组相比（平均值为3125±298道尔顿/分钟/毫克蛋白质），长期给予利坦色林或氯吉兰对[3H]InsP积累的基础水平没有影响。利坦色林在5-HT浓度为1微摩尔、100微摩尔和1毫摩尔时可增加5-HT刺激的[3H]InsP积累，且在5-HT浓度为100微摩尔时这种影响具有显著性。氯吉兰在5-HT浓度为1微摩尔、100微摩尔和1毫摩尔时对5-HT刺激的[3H]InsP积累没有显著或一致的影响。因此，长期给予氯吉兰和利坦色林对与5-HT2相关的肌醇磷脂水解的影响与其对5-HT2受体数量（Bmax）的影响不相关。由于利坦色林可显著增加磷脂酰肌醇（PtdIns）、磷脂酰肌醇4-磷酸（PtdIns4P）和磷脂酰肌醇4,5-二磷酸（PtdIns(4,5)P2）的标记，而氯吉兰可显著增加PtdIns和PtdIns4P的标记，情况变得更加复杂。本文讨论了其意义。
