EFFECT OF ACUTE AND PROLONGED TIANEPTINE ADMINISTRATION ON THE 5-HT TRANSPORTER - ELECTROPHYSIOLOGICAL, BIOCHEMICAL AND RADIOLIGAND BINDING-STUDIES IN THE RAT-BRAIN
G. Pineyro et al., EFFECT OF ACUTE AND PROLONGED TIANEPTINE ADMINISTRATION ON THE 5-HT TRANSPORTER - ELECTROPHYSIOLOGICAL, BIOCHEMICAL AND RADIOLIGAND BINDING-STUDIES IN THE RAT-BRAIN, Naunyn-Schmiedeberg's archives of pharmacology, 351(2), 1995, pp. 111-118
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.