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Effects of tianeptine and other antidepressants on the activity of medial septal neurons in rats anesthetized with urethane
402 also tested for their ability to interact with CNS receptors (see Thomas et al, 1987; Sanger and Nelson, 1989, for methods). Paroxetine was the most potent serotonin re-uptake inhibitor (Ki=l.l+0.1 nM) possessing a high degree of selectivity relative to NA uptake (serotonin/N'A selectivity ratio=320) and DA uptake (serotonin/DA selectivity ratio=2500). Of the other drugs tested, fluoxetine was 23-fold less potent than paroxetine at inhibiting serotonin uptake as well as exhibiting only a 20-fold selectivity versus NA uptake. Sertraline, as a serotonin uptake inhibitor was 6.6 times less potent than paroxetine, and showed only moderate selectivity with respect to DA uptake (serotonin/DA selectivity ratio=45). Paroxetine inhoboted [3I-I]-serotonin uptake (EDs0=l.2 mg/kg) when measured two hours after acute oral administration in rats, being about 5 times more potent than fluoxetine (ED50=5.8 mg/kg) and about twice as potent as sertraline (ED50~2.7 mg/kg). None of the SSRIs tested inhibited the uptake of [3H]-NA or [3H]-DA at 30 mg/kg by 50% or more under these ex vivo conditions. Compared with its high potency for serotonin re-uptake inhibition, paroxetine shows a notable lack of affinity at a wide range of CNS receptors, including alpha- and beta-adrenoceptors, 5-HT l, 5-HT 2, 5-HT 3, DA or histamine l receptors. Published evidence indicates that fluoxetine and sertraline similarly show little or no affinity for these receptors. In conclusion, paroxetine is a more potent and a selective serolonin re-uptake inhibitor than fluoxetine and sertraline. Compared with paroxetine, fluoxetine shows less selectivity with respect to NA uptake while sertraline is less selective with regard to DA uptake in vitro. The lack of interaction of paroxetine, fluoxetine and sertraline with CNS receptors supports the contention that these antidepressants are devoid of the side effects normally associated with the tricyclie class. References Thomas, D.R., Nelson, D.R., Johnson A.M., 1987. Psychopharmacology 93, 193. Sanger, O.J. and Nelson, D.R., 1989, Europ. J. Pharmaeol. 159, 113.
Effects of tianeptine and other antidepressants on the activity of medial septal neurons in rats anesthetized with urethane
Bassant, M.H.*, Lee, B.H.**, Jazat, F.*, Lamour, Y.* and Mocaer, E.*** *INSERM U. 161, 2 rue d'Aldsia, 75014 Paris, France, **Department of Physiology, College of Medicine, Korea University, Seoul, Korea, and ***IRIS, 6 place des Pldiades, 92415 Courbevoie, France Tianeptine is a tricyclie antidepressant which enhances serotonin uptake in certain brain areas (Mennini et al, 1987). Tianeptine has been reported to improve both working and reference memory in rodents (Jaffard et al, 1991). Mechanisms by which tianeptine can exert a facilitating effect on memory are not understood. In the present work, we investigated the effects of tianepline on neurons of the medial septal area t/VISA). The MSA contains neurons which innervate the hippocampus. A significant proportion of the neurons are cholinergic and are likely to be involved in learning and memory (Thomas et al, 1989). Sprague-Dawley rats were anesthetized with urethane. Systemic administrations (0.2 - 1 mg/kg, i.v.) of tianeptine decreased the spontaneous activity and disorganized or suppressed the rythmically bursting activity (RBA) of medial septal neurons, in a dose related manner. Iontophoretic administrations of tianeptine did not modify the spontaneous activity of medial septal neurons. Changes in RBA were inconsistent. However, tianeptine blocked partially or completely 5-HT-induced inhibition in 68% of the cases. It had no effect on the noradrenaline-induced inhibition. In contrast, other antidepressants (amitriptyline, clomipramine and fluoxetine) potentiated the inhibitory effect of 5-HT to 60% of the cases. Our results show that tianeptine, applied by iontophoresis, has an effect on the medial septal neurons which is opposite to that of more classical antidepressants. On the basis of our findings, it can be tentatively proposed that
403 tianeptine may have a beneficial effect on memory by counteracting the 5-HT-induced inhibition of medial septal neurons. References Mennini, T., Mocaer, E. and Garattini, S., 1987, Tianeptine, a selective enhancer of serotonin uptake in rat brain. NaunynSehmiedeberg's Arch. Pharmacol. 336, 478-482. laffard, R., Mocaer, E., Poignant, J.C., Micheau, J., Marighetto, A., Meunier, M. and Beracochea, D., 1991, Effects of tianeptine on spontaneous alternation, simple and concurrent spatial discrimination learning and on sequential alternation deficits induced by longterm ethanol administration in mice. Behav. Pharmacol. 2, 37-47. Thomas, G.J., Brito, G.N.O., Stein, D.P. and Berko, J.K., 1982, Memory and septohippoeampal connections in rats. J. Comp. Physiol. Psychol. 96, 339-347.
Effects of the thiadiazolo-quinoline derivative RP 68303, a novel serotonin (5-1:IT) uptake inhibitor, on behaviour and sleep parameters in rodents Piot, 0., B6hme, G.A., Blanchard, J.C. and Stutzmann, J.M. Rhone-Poulenc Rorer, Psychopharmacology and Electrophysiology Units, Vitry Research Center, 94403 Vitry-sur-Seine Cedex, France Key words: Behavioural pharmacology, Sleep-wakefulness cycles, 5-HT uptake inhibitor, Rodents Certain recognized antidepressants, such as fluoxetine, fluvoxamine and indalpine potently and specifically inhibit neuronal 5-HT reuptake; in the absence of other major pharmacological effects, it appears that their antidepressive activity stems from facilitation of 5-HT neurotransmission as a result of reuptake inhibition. These compounds are known to potentiate the behavioural manifestations induced by the 5-HT precursor, 5-hydroxytryptophan (5-HTP). Moreover, both serotonergic and classical tricyelie antidepressants decrease the amount and delay the onset of rapid-eyemovement (REM) sleep in animals and humans. RP 68303 (a thiadiazolo (4,3,2-ij) quinoline-2,2 dioxide derivative) is a novel specific and potent 5-HT uptake inhibitor showing high affmity for [3H]-paroxetine binding sites (1.4 nM). To further characterize RP 68303, we studied its activity in behaviofiral serotonergic models. We also investigated its effect on the sleep/wakefulness cycles of rats. For the behavioural studies, groups of 6 Swiss mice or Wistar rats were orally administered vehicle (1% Tween), a suspension of RP 68303 or a suspension of fluoxetine, 90 min (mice) or 60 mln (rats, before being treated intraperitoneally with 100 mg.kg q 5-HTP. RP 68303 appeared more potent than fluoxetine in potentiating 5-HTP-induced behavioral manifestations in mice (EDs0s of 2.9 and 7.5 mg.kg "l, respectively). No evidence for tolerance was observed upon subehronie treatment, the EDs0 for RP 68303 remaining at 3.6 mg.kg l after 5 days. RP 68303 and fluoxetine also potentiated the serotonin syndrome in rats with EDs0s of 15 and 8.7 mg.kg "l, respectively. Furthermore, RP 68303 did not potentiate the effects of alcohol and barbiturates, and did not induce motor impairment in the rota-rod test in mice at doses as high as 160 mg.kg"l. For the sleep/wakefulness studies, the electroeorticogramme and eleetromyogramme of Sprague-Dawley rats were recorded and analysed on-line using a computer-based vigilance stage classifier. During daily 7-hour recording sessions, ervery consecutive 20-see period was automatically classified as being spent awake, in intermediate sleep (IS, in slow-wave sleep (SWS) or in REM-sleep. Data collected on day 1 (control), day 2 (treatment) and day 3 (the day after treatment) were statistically assessed using a paired t-test. The oral administration of RP 68303 (5-20 mg.kg "l) did not significantly modify the duration of wakefulness or SWS, or the latency of the first SWS-episode, but increased IS-duration. The number of REM-sleep episodes (-28%, NS; -72%, P<0.01 and -58%, P<0.01 after 5, 10 and 20 mg/kgl , respectively) and the mean REM-sleep duration (-33%, NS; -85%, P<0.05 and -60%, P<0.05) decreased, while the REM-sleep latency increased in a dose-dependent manner (+79%, NS; +268%, P<0.01 and +322%, P<0.05). On day 3, no clearcut alteration of the sleep/wakefulness parameters was observed. These results indicate that RP 68303 may be a useful drug for the treatment of depression.
Effects of tianeptine and other antidepressants on the activity of medial septal neurons in rats anesthetized with urethane
Bassant, M.H.*, Lee, B.H.**, Jazat, F.*, Lamour, Y.* and Mocaer, E.*** *INSERM U. 161, 2 rue d'Aldsia, 75014 Paris, France, **Department of Physiology, College of Medicine, Korea University, Seoul, Korea, and ***IRIS, 6 place des Pldiades, 92415 Courbevoie, France Tianeptine is a tricyclie antidepressant which enhances serotonin uptake in certain brain areas (Mennini et al, 1987). Tianeptine has been reported to improve both working and reference memory in rodents (Jaffard et al, 1991). Mechanisms by which tianeptine can exert a facilitating effect on memory are not understood. In the present work, we investigated the effects of tianepline on neurons of the medial septal area t/VISA). The MSA contains neurons which innervate the hippocampus. A significant proportion of the neurons are cholinergic and are likely to be involved in learning and memory (Thomas et al, 1989). Sprague-Dawley rats were anesthetized with urethane. Systemic administrations (0.2 - 1 mg/kg, i.v.) of tianeptine decreased the spontaneous activity and disorganized or suppressed the rythmically bursting activity (RBA) of medial septal neurons, in a dose related manner. Iontophoretic administrations of tianeptine did not modify the spontaneous activity of medial septal neurons. Changes in RBA were inconsistent. However, tianeptine blocked partially or completely 5-HT-induced inhibition in 68% of the cases. It had no effect on the noradrenaline-induced inhibition. In contrast, other antidepressants (amitriptyline, clomipramine and fluoxetine) potentiated the inhibitory effect of 5-HT to 60% of the cases. Our results show that tianeptine, applied by iontophoresis, has an effect on the medial septal neurons which is opposite to that of more classical antidepressants. On the basis of our findings, it can be tentatively proposed that
403 tianeptine may have a beneficial effect on memory by counteracting the 5-HT-induced inhibition of medial septal neurons. References Mennini, T., Mocaer, E. and Garattini, S., 1987, Tianeptine, a selective enhancer of serotonin uptake in rat brain. NaunynSehmiedeberg's Arch. Pharmacol. 336, 478-482. laffard, R., Mocaer, E., Poignant, J.C., Micheau, J., Marighetto, A., Meunier, M. and Beracochea, D., 1991, Effects of tianeptine on spontaneous alternation, simple and concurrent spatial discrimination learning and on sequential alternation deficits induced by longterm ethanol administration in mice. Behav. Pharmacol. 2, 37-47. Thomas, G.J., Brito, G.N.O., Stein, D.P. and Berko, J.K., 1982, Memory and septohippoeampal connections in rats. J. Comp. Physiol. Psychol. 96, 339-347.
Effects of the thiadiazolo-quinoline derivative RP 68303, a novel serotonin (5-1:IT) uptake inhibitor, on behaviour and sleep parameters in rodents Piot, 0., B6hme, G.A., Blanchard, J.C. and Stutzmann, J.M. Rhone-Poulenc Rorer, Psychopharmacology and Electrophysiology Units, Vitry Research Center, 94403 Vitry-sur-Seine Cedex, France Key words: Behavioural pharmacology, Sleep-wakefulness cycles, 5-HT uptake inhibitor, Rodents Certain recognized antidepressants, such as fluoxetine, fluvoxamine and indalpine potently and specifically inhibit neuronal 5-HT reuptake; in the absence of other major pharmacological effects, it appears that their antidepressive activity stems from facilitation of 5-HT neurotransmission as a result of reuptake inhibition. These compounds are known to potentiate the behavioural manifestations induced by the 5-HT precursor, 5-hydroxytryptophan (5-HTP). Moreover, both serotonergic and classical tricyelie antidepressants decrease the amount and delay the onset of rapid-eyemovement (REM) sleep in animals and humans. RP 68303 (a thiadiazolo (4,3,2-ij) quinoline-2,2 dioxide derivative) is a novel specific and potent 5-HT uptake inhibitor showing high affmity for [3H]-paroxetine binding sites (1.4 nM). To further characterize RP 68303, we studied its activity in behaviofiral serotonergic models. We also investigated its effect on the sleep/wakefulness cycles of rats. For the behavioural studies, groups of 6 Swiss mice or Wistar rats were orally administered vehicle (1% Tween), a suspension of RP 68303 or a suspension of fluoxetine, 90 min (mice) or 60 mln (rats, before being treated intraperitoneally with 100 mg.kg q 5-HTP. RP 68303 appeared more potent than fluoxetine in potentiating 5-HTP-induced behavioral manifestations in mice (EDs0s of 2.9 and 7.5 mg.kg "l, respectively). No evidence for tolerance was observed upon subehronie treatment, the EDs0 for RP 68303 remaining at 3.6 mg.kg l after 5 days. RP 68303 and fluoxetine also potentiated the serotonin syndrome in rats with EDs0s of 15 and 8.7 mg.kg "l, respectively. Furthermore, RP 68303 did not potentiate the effects of alcohol and barbiturates, and did not induce motor impairment in the rota-rod test in mice at doses as high as 160 mg.kg"l. For the sleep/wakefulness studies, the electroeorticogramme and eleetromyogramme of Sprague-Dawley rats were recorded and analysed on-line using a computer-based vigilance stage classifier. During daily 7-hour recording sessions, ervery consecutive 20-see period was automatically classified as being spent awake, in intermediate sleep (IS, in slow-wave sleep (SWS) or in REM-sleep. Data collected on day 1 (control), day 2 (treatment) and day 3 (the day after treatment) were statistically assessed using a paired t-test. The oral administration of RP 68303 (5-20 mg.kg "l) did not significantly modify the duration of wakefulness or SWS, or the latency of the first SWS-episode, but increased IS-duration. The number of REM-sleep episodes (-28%, NS; -72%, P<0.01 and -58%, P<0.01 after 5, 10 and 20 mg/kgl , respectively) and the mean REM-sleep duration (-33%, NS; -85%, P<0.05 and -60%, P<0.05) decreased, while the REM-sleep latency increased in a dose-dependent manner (+79%, NS; +268%, P<0.01 and +322%, P<0.05). On day 3, no clearcut alteration of the sleep/wakefulness parameters was observed. These results indicate that RP 68303 may be a useful drug for the treatment of depression.