Chronic amitriptyline exposure reduces 5-HT3 receptor-mediated cyclic GMP formation in NG 108-15 cells.
In the present study, we investigated the effects of chronic in vitro administration of amitriptyline, a tricyclic antidepressant, on cyclic GMP formation stimulated by 5-hydroxytryptamine (5-HT) in the neuroblastoma x glioma hybrid cell line, NG 108-15, 5-HT (0.01-100 microM)-stimulated cyclic GMP formation was concentration-dependent and was sensitive to ICS 205-930, a 5-HT3 receptor antagonist. Exposure of NG 108-15 cells to 5 microM amitriptyline for 3 days significantly reduced 5-HT-stimulated cyclic GMP formation. Acute treatment with amitriptyline had no effect on 5-HT-stimulated cyclic GMP formation. The reduction by chronic amitriptyline exposure of 10 microM 5-HT-stimulated cyclic GMP formation was concentration-dependent over the concentration range examined (0.5 to 10 microM). The IC50 of amitriptyline was 1.9 microM. In contrast, amitriptyline exposure, even at a concentration of 8 microM, failed to modify cyclic GMP formation stimulated by bradykinin, sodium nitroprusside, or atrial natriuretic peptide. Increases in intracellular Ca2+ concentration ([Ca2+]i) evoked by 10 microM 5-HT were attenuated in amitriptyline-exposed cells, while 100 nM bradykinin-induced [Ca2+]i increases were not affected. In addition, chronic exposure to 5 microM amitriptyline caused a decrease in affinity (Kd) of [3H]zacopride specific binding to 5-HT3 recognition sites. The Bmax for the labelled ligand remained unchanged. These results suggest that chronic amitriptyline exposure reduces 5-HT-stimulated cyclic GMP formation and [Ca2+]i increases, and this may reflect the functional changes of 5-HT3 receptors.
Shimizu
M
M
Department of Psychiatry and Neuroscience, Kure National Hospital, Japan.
Nishida
A
A
Zensho
H
H
Yamawaki
S
S
D000639:Amitriptyline / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001549:Benzamides / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology; D001932:Brain Neoplasms / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis*; D005456:Fluorescent Dyes; D016257:Fura-2; D005910:Glioma / Q000473:pathology; D006822:Hybrid Cells; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D009447:Neuroblastoma / Q000473:pathology; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology; D000077526:Tropisetron; D014407:Tumor Cells, Cultured
D000929:Antidepressive Agents, Tricyclic; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005456:Fluorescent Dyes; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D000639:Amitriptyline; D000077526:Tropisetron; C055971:zacopride; D006152:Cyclic GMP; D001920:Bradykinin; D002118:Calcium; D016257:Fura-2