慢性阿米替林治疗后NG 108-15细胞中5-羟色胺介导的环磷酸腺苷积累增强。

Enhancement of cyclic AMP accumulation mediated by 5-HT after chronic amitriptyline treatment in NG 108-15 cells.

作者信息

Shimizu M, Nishida A, Fukuda H, Saito H, Yamawaki S

机构信息

Department of Psychiatry and Neuroscience, Kure National Hospital, Japan.

出版信息

Br J Pharmacol. 1995 Mar;114(6):1282-8. doi: 10.1111/j.1476-5381.1995.tb13344.x.

DOI:10.1111/j.1476-5381.1995.tb13344.x

PMID:7620719

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1510362/

Abstract

The effects of chronic in vitro administration of amitriptyline, a tricyclic antidepressant, on 5-hydroxytryptamine (5-HT) receptor-mediated adenylyl cyclase activity was studied in the neuroblastoma x glioma hybrid cell line, NG 108-15. 2. Treatment of NG 108-15 cells with 8 microM amitriptyline for 3 days increased forskolin-stimulated (0.1 microM) adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation. Addition of 5-HT (0.1-100 microM) increased forskolin-stimulated cyclic AMP accumulation in amitriptyline-treated cells in a concentration-dependent manner. However, 5-HT did not affect forskolin-stimulated cyclic AMP accumulation in untreated cells. 3. The 5-HT4 receptor agonist, 5-methoxytryptamine, significantly enhanced forskolin-stimulated cyclic AMP accumulation in amitriptyline-treated cells. In contrast, amitriptyline treatment failed to modify 8-hydroxy-2-(di-n-propylamine) tetralin-induced inhibition of forskolin-stimulated cyclic AMP accumulation. 4. Pretreatment of cells with pertussis toxin did not affect the 5-HT-induced enhancement of cyclic AMP accumulation. 5. The 5-HT-induced enhancement of cyclic AMP accumulation in amitriptyline-treated cells was attenuated by the 5-HT4 receptor antagonists, GR 113808 and ICS 205-930, with relatively low potency. However, spiperone, SCH 23390, and pindolol were completely ineffective against this 5-HT-induced enhancement. 6. Chronic treatment with amitriptyline did not modify the cyclic AMP production stimulated by prostaglandin E1 or cholera toxin. This treatment also had no effect on GTP gamma S-, NaF-, and Mn(2+)-stimulated cyclic AMP accumulation in isolated cell membranes. 7. Chronic treatment with the 5-HT receptor antagonists, pindolol or ICS 205-930, did not inhibit the 5-HT-induced enhancement of cyclic AMP accumulation.8. Chronic treatment with other antidepressant drugs, imipramine, mianserin or paroxetine, elicited the 5-HT-induced enhancement of cyclic AMP accumulation.9. Taken together, these results suggest that chronic amitriptyline treatment of NG 108-15 cells causes 5-HT to enhance forskolin-stimulated cyclic AMP accumulation by enhancing 5-HT receptor-mediated stimulation of adenylyl cyclase and not by reducing 5-HT-mediated inhibition of adenylyl cyclase. The 5-HT-induced enhancement of cyclic AMP accumulation in amitriptyline-treated cells may result from changes at the level of the 5-HT receptor rather than at the level of G, proteins or adenylyl cyclase. It is unlikely that this enhancement of cyclic AMP accumulation is caused by long-term antagonism of the 5-HT receptor by amitriptyline.

摘要

研究了三环类抗抑郁药阿米替林长期体外给药对神经母细胞瘤x胶质瘤杂交细胞系NG 108 - 15中5 - 羟色胺（5 - HT）受体介导的腺苷酸环化酶活性的影响。2. 用8微摩尔/升阿米替林处理NG 108 - 15细胞3天，可增加福斯高林（0.1微摩尔/升）刺激的3':5'-环磷酸腺苷（环磷酸腺苷）积累。添加5 - HT（0.1 - 100微摩尔/升）可使阿米替林处理的细胞中福斯高林刺激的环磷酸腺苷积累呈浓度依赖性增加。然而，5 - HT对未处理细胞中福斯高林刺激的环磷酸腺苷积累没有影响。3. 5 - HT4受体激动剂5 - 甲氧基色胺显著增强了阿米替林处理细胞中福斯高林刺激的环磷酸腺苷积累。相比之下，阿米替林处理未能改变8 - 羟基 - 2 -（二正丙胺）四氢萘诱导的对福斯高林刺激的环磷酸腺苷积累的抑制作用。4. 用百日咳毒素预处理细胞不影响5 - HT诱导的环磷酸腺苷积累增强。5. 5 - HT4受体拮抗剂GR 113808和ICS 205 - 930可减弱阿米替林处理细胞中5 - HT诱导的环磷酸腺苷积累增强，但效力相对较低。然而，螺哌隆、SCH 23390和吲哚洛尔对这种5 - HT诱导的增强作用完全无效。6. 阿米替林长期处理未改变前列腺素E1或霍乱毒素刺激的环磷酸腺苷产生。这种处理对分离细胞膜中GTPγS、NaF和Mn(2 +)刺激的环磷酸腺苷积累也没有影响。7. 5 - HT受体拮抗剂吲哚洛尔或ICS 205 - 930长期处理不抑制5 - HT诱导的确环磷酸腺苷积累增强。8. 用其他抗抑郁药丙咪嗪、米安色林或帕罗西汀长期处理可引发5 - HT诱导的环磷酸腺苷积累增强。9. 综上所述，这些结果表明，对NG 108 - 15细胞进行长期阿米替林处理可使5 - HT通过增强5-HT受体介导的腺苷酸环化酶刺激作用而非通过减少5 - HT介导的腺苷酸环化酶抑制作用来增强福斯高林刺激的环磷酸腺苷积累。在阿米替林处理的细胞中，5 - HT诱导的环磷酸腺苷积累增强可能是由于5 - HT受体水平的变化，而非G蛋白或腺苷酸环化酶水平的变化。环磷酸腺苷积累的这种增强不太可能是由阿米替林对5 - HT受体的长期拮抗作用引起的。