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Enhancement of cyclic AMP accumulation mediated by 5‐HT after chronic amitriptyline treatment in NG 108‐15 cells
Author(s) -
Shimizu Masami,
Nishida Akira,
Fukuda Hiroyuki,
Saito Hiroshi,
Yamawaki Shigeto
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb13344.x
Subject(s) - forskolin , adenylyl cyclase , endocrinology , medicine , amitriptyline , pertussis toxin , chemistry , cholera toxin , adenosine , agonist , pharmacology , receptor , stimulation , g protein , biology
1 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 μ m amitriptyline for 3 days increased forskolin‐stimulated (0.1 μ m ) adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) accumulation. Addition of 5‐HT (0.1–100 μ m ) 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‐HT 4 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‐HT 4 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 E 1 or cholera toxin. This treatment also had no effect on GTP γ 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 s 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.