CHRONIC AMITRIPTYLINE EXPOSURE REDUCES 5-HT3 RECEPTOR-MEDIATED CYCLICGMP 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 neurobl astoma x glioma hybrid cell line, NG 108-15, 5-HT (0.01-100 mu M)-stim ulated cyclic GMP formation was concentration-dependent and was sensit ive to ICS 205-930, a 5-HT3 receptor antagonist. Exposure of NG 108-15 cells to 5 mu M amitriptyline for 3 days significantly reduced 5-HT-s timulated cyclic GMP formation. Acute treatment with amitriptyline had no effect on 5-HT-stimulated cyclic GMP formation. The reduction by c hronic amitriptyline exposure of 10 mu M 5-HT-stimulated cyclic GMP fo rmation was concentration-dependent over the concentration range exami ned (0.5 to 10 mu M). The IC50 of amitriptyline was 1.9 mu M. In contr ast, amitriptyline exposure, even at a concentration of 8 mu M, failed to modify cyclic GMP formation stimulated by bradykinin, sodium nitro prusside, or atrial natriuretic peptide. Increases in intracellular Ca 2+ concentration ([Ca2+](i)) evoked by 10 mu M 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 mu M amitriptyline caused a decrease in affinity (K-d) of [H-3]zacopride s pecific binding to 5-HT3 recognition sites. The B-max for the labelled ligand remained unchanged. These results suggest that chronic amitrip tyline exposure reduces 5-HT-stimulated cyclic GMP formation and [Ca2](i) increases, and this may reflect the functional changes of 5-HT3 r eceptors.