EFFECT OF ACUTE AND PROLONGED TIANEPTINE ADMINISTRATION ON THE 5-HT TRANSPORTER - ELECTROPHYSIOLOGICAL, BIOCHEMICAL AND RADIOLIGAND BINDING-STUDIES IN THE RAT-BRAIN

In the present study, in vivo extracellular unitary recordings, in vit ro [H-3]5-HT uptake and [H-3]cyanoimipramine binding assays were used to assess the effect of acute and prolonged administration of the puta tive antidepressant tianeptine, on the 5-hydroxytryptamine (5-HT) tran sporter. Microiontophoretic application of tianeptine onto dorsal hipp ocampus CA(3) pyramidal neurons, as well as its intravenous administra tion (2 mg/kg), increased their firing frequency. Following intracereb roventricular administration of 5,7-dihydroxytryptamine, the activatio n induced by the microiontophoretic application of tianeptine remained unchanged, thus suggesting that the 5-HT carrier is not involved in t his effect. Furthermore, in spite of its activating effect on CA(3) py ramidal neuron firing frequency, the intravenous administration of tia neptine did not alter the time of recovery of these neurons from micro iontophoretic applications of 5-HT, an index of 5-HT uptake activity. In keeping with this observation, the acute administration of tianepti ne did not change the effectiveness of the 5-HT reuptake blocker parox etine (1 mg/kg, i.v.) in prolonging the suppressant effect of microion tophoretically-applied 5-HT. However, in rats that had received tianep tine for 14 days (20 mg/kg/day, s.c.), the recovery time from the supp ressant effect of microiontophoretic applications of 5-HT was reduced by 40% and the effectiveness of paroxetine (1 mg/kg, i.v.) was decreas ed. These effects were no longer observed following a 48 h washout per iod. In a second series of experiments, the ability of tianeptine to i nterfere with the uptake blocking capacity of paroxetine was assessed in vitro, using hippocampal slices obtained from rats that had been tr eated with tianeptine for 14 days (20 mg/kg/day, s.c.; by minipump). T he effectiveness of paroxetine to block [H-3]5-HT uptake was unchanged in slices obtained from rats still bearing the osmotic minipump at th e time of the sacrifice, as well as from those which had undergone a 4 8 h washout period. To assess whether prolonged administration of tian eptine would induce adaptive changes on 5-HT uptake sites, [H-3] cyano imipramine-binding parameters were measured following a 48 h washout p eriod. Affinity values remained unchanged while density values were si gnificantly increased in cortex (+22%) but not in hippocampus (+12%). It is concluded that, i) the activation of CA(3) pyramidal neurons obs erved following acute tianeptine administration cannot be attributed t o its 5-HT uptake enhancing properties and ii) the prolonged administr ation of tianeptine induces adaptive changes on cortical but not on hi ppocampal 5-HT transporters.