Effects of tianeptine on spontaneous alternation, simple and concurrent spatial discrimination learning and on alcohol-induced alternation deficits in mice.

The effects of systemic administration of tianeptine, a new psychotropic agent with antidepressant properties, were investigated on spontaneous alternation behavior, and on simple and concurrent spatial discrimination, in normal mice of the BALB/c strain. Tianeptine increased rates of spontaneous T-maze alternation, facilitated retention of a T-maze left-right discrimination, and speeded up acquisition of concurrent discrimination in a radial maze. These effects were consistent across successive experiments with a dose of 10mg/kg; lower doses (2.5 and 5.0mg/kg) had less or no effect depending on the task. These results, together with theoretical considerations, led us to investigate the effect of tianeptine on the sequential-specific alternation deficit induced by long-term ethanol administration in the same strain of mice. Results showed that, at the dose of 10mg/kg, the drug completely alleviated the alcohol-induced deficit. Unlike tianeptine, fluoxetine impaired discrimination performance in the radial maze. These data are discussed in light of the effects of tianeptine on serotonergic transmission and of the role of serotonin and acetylcholine in learning and memory processes.

Structure-activity relationships of tricyclic antidepressants, with special reference to tianeptine.

Structure-activity relationships in the classical antidepressant (imipramine-like) series show a relative lack of specificities: Compounds should simply have a nucleus consisting of two phenyl rings and a third, seven-member central ring. This central ring may have one, several, or no heteroatoms, and it may or may not be saturated. The side chain may be attached to any one of the atoms of the central ring, but it must be short (two or three carbon atoms), and have a terminal amine group (secondary, tertiary, or included in a ring). We investigated the structure-activity relationships of 22 new tricyclic tianeptine derivatives exhibiting reserpine-induced ptosis reversal potency in the mouse. Tianeptine is an antidepressant characterized by a 3-chlorodibenzothiazepin nucleus and an aminoheptanoic side chain. Our results indicate highly specific structural requirements for the tianeptine-like series. In order to be active, compounds must have an aminocarboxylic chain (with an optimal length of six methylene links), a tricyclic system with an electron-donor heteroatom in position 5, and an aromatic substitution with a moderate electron-acceptor atom in position 3. These specificities in the tianeptine series are in sharp contrast with the lack of specific requirements that characterize the classical tricyclic series.

Apomorphine and piribedil in rats: biochemical and pharmacologic studies.

We studied the biochemical and pharmacologic modes of action of piribedil and apomorphine in the rat. Although both drugs have many points in common, they are also different in many of their manifestations. Apomorphine causes high-intensity, short-duration stereotyped behavior; it is distributed within the brain in uneven fashion, the striatum being the area of lowest concentration as measured by fluorometry. Direct stereotactic injection within the dopaminergic mesolimbic system, and particularly the tuberculum olfactorium, produced constant intense responses. All effects of apomorphine can be blocked by pimozide, but propanolol, a beta blocker, only reduces aggression and ferocity, leaving stereotyped behaviors intact. Finally, L-5-HTP tends to reduce aggression, ferocity, and to a lesser extent stereotypy; MIF or piribedil, as well as reserpine, potentiates the stereotyped behaviors induced by apomorphine, whereas L-DOPA usually decreases them. Piribedil, on the other hand, causes low-intensity, long-duration stereotyped behavior. It is distributed within the brain almost uniformly. Most effects of piribedil can be blocked by pimozide, but propanolol blocks only aggression and ferocity, leaving stereotyped behaviors intact. On the other hand, clonidine, an alpha-receptor agonist, blocks stereotyped behaviors induced by piribedil but markedly increases aggression, ferocity, and motor activity. L-5-HTP and L-DOPA have little effect on piribedil-induced manifestations. Reserpine decreases piribedil stereotypy. The main metabolite of piribedil, S 584, had no clear-cut pharmacologic action in our hands at the dosage used. It is concluded that both apomorphine and piribedil produce stereotyped behavior by modifying the physiologic balance between mesolimbic and nigrostriatal dopaminergic systems. The other actions of apomorphine and piribedil upon aggression, ferocity, and motor activity are not always in parallel and depend probably on the fact that piribedil is less specific, affecting also noradrenergic, serotonergic, histaminergic, and/or cholinergic circuits. The usefulness of piribedil against some forms of human tremor and its low-intensity antiakinetic action probably result from this pattern of pharmacologic activity.

Amineptine improves the performance of dogs in a complex temporal regulation schedule.

Amineptine is a tricyclic antidepressant with activating properties, that stimulates spontaneous locomotor activity in rodents and elevates mood in humans. It mainly inhibits dopamine uptake and weakly increased dopamine release. Formulating the hypothesis that this drug would decrease waiting capacity, we decided to test amineptine in a Differential Reinforcement of Response Duration schedule (DRRD 9 s Limited Hold 1.5 s) in the dog. The drug was administered orally at 2.5, 5.0, 7.5, 10 and 20 mg/kg, 1 h before the experimental session. Between 2.5 and 10 mg/kg, amineptine improved the performance by increasing the response (nonsignificantly) and reinforcement (significantly) rates and by increasing the peak of correct responses (significantly). The inverse effect was measured for the reinforcement rate (nonsignificantly) and for the peak of correct responses (significantly) at the dose of 20 mg/kg. These results were compared to those obtained with other classes of drugs, like neuroleptics, barbiturates or anxiolytics, that disturbed the performance, and particularly with low doses of neuroleptics, which also increase the dopamine release. The positive effects of amineptine on performance (2.5-10 mg/kg) were related to its inhibitory effect on dopamine uptake and discussed in terms of improved vigilance and attention, increase of waiting capacity, improved anticipation, and cognitive enhancement.

Amineptine, response timing, and time discrimination in the albino rat.

Experiment 1 recorded the effects of single (doses of 1, 5, 10, and 20 mg/kg) and repeated intraperitoneal injections (10 mg/kg) of amineptine (a tricyclic antidepressant drug) on the performance of albino rats in differential reinforcement of low rate (DRL) of 30 s, fixed-interval (FI) of 60 s, and signalled continuous reinforcement (CRF-SD) schedules. In the second experiment, the effects of repeated (10 mg/kg) and single injections (20 mg/kg) were assessed on the discrimination of the duration of auditory stimuli (2 and 8 s). A dose-related increase in response rates was observed in FI and DRL, correlating with a dose-related impairment in the temporal regulation of performance. However, the drug remained without effect on duration discrimination. In other respects, decreases in response latency in CRF-SD or duration discrimination tended to indicate that the drug improved vigilance and reactivity to extraneous significant stimuli. Interpretations in terms of sensitization, tolerance, or dependency could be discarded. Our data support the hypothesis that drug effects on temporal regulation in FI and DRL are secondary to a nonspecific activation of motor activity. They question the plausibility of an antidepressant effect of the drug in humans via modulation of a timing mechanism.

[Electrophysiological study of tianeptine, a new enhancer of serotonin uptake with antidepressant activity]. / Etude électrophysiologique de la tianeptine, nouveau stimulant du recaptage de la sérotonine possédant une activité antidépressive.

Tianeptine is a clinically effective antidepressant, not chemically related to classical tricyclic compounds. Its mechanism of action preferentially involves central serotoninergic transmissions, by increasing uptake after acute and chronic administration in rat brain and platelets and in human platelets. We studied the effects of tianeptine on three currently used electrophysiological methods: Ro4-1284 induced PGO waves in the cat, neocortical EEG activity in the acute rat preparation and sleep-wakefulness modifications in chronically implanted rats. Density of Ro4-1284 induced PGO waves was reduced by tianeptine, the minimal effective dose being 2 mg.kg-1i.v. (ED50 = 2.9 mg.kg-1i.v.). In acute rat preparation, the low voltage fast waves basal EEG pattern was not modified by tianeptine in a dose range of 1.25 to 20 mg.kg-1i.p. Higher dosage (25 mg.kg-1i.p.) induced high amplitude episodes with few or no delta waves. Low doses which did not apparently modify acute EEG have been tested on sleep-wakefulness cycle in implanted rats. Tianeptine, after single administration, did not modify sleep states up to 2.5 mg.kg-1i.p. An increased wakefulness was observed during the first hour after 5-10 mg.kg-1i.p., afterwards sleep states returned to control values up to 12 h. A subsequent 12 h recording performed 24 h after treatment did not show any change compared to pretreatment baseline. After sub-chronic administration (2.5 mg.kg-1i.p./day, 9 days) no change was observed in sleepwake pattern during or after cessation of treatment. Tianeptine EEG profile is radically different from those usually induced by classical tricyclic antidepressants.

[Amineptine, a new antidepressant: pharmacological review (author's transl)]. / Revue pharmacologique sur l'amineptine.

Amineptine is a tricyclic derivative with a 7-carbon chain of aminoacids. Chemical alterations of the aminoacid chain have revealed its importance in the shaping of the pharmacological effects. The drug is rapidly absorbed. Amineptine is metabolised principally by beta-hydroxylation of the chain. The pharmacological profile at different doses is as follows: a. 0.1 mg/kg: reduction of exploratory behaviour, b. 1 mg/kg: reduction of serum prolactin level, c. 5 mg/kg: potentiation of L-5 HTP, d. 10 mg/kg: antagonism of the effects of reserpine and of tetrabenazine, e. increased activity and social behaviour, EEG alerting effect limited to 1 hour and increase in paradoxical sleep (15 to 20 mg/kg). This pharmacological profile suggests an effect of amineptine upon certain dopamine structures. At synapse, neurobiochemistry confirms a mechanism of inhibition of DA incorporation and inhibition of uptake and/or release of 5 HT. Amineptine is virtually devoid of peripheral activity, particularly anticholinergic Amineptine may be indicated for the treatment of depression where retardation is dominant.

[Contribution of electrophysiology to the study of tianeptine and other antidepressive agents]. / Apport de l'électrophysiologie à l'étude de la tianeptine et d'autres antidépresseurs.

Intravenous perfusion of tianeptine reduces the frequency of coeruleus locus neural discharge. It does not affect the rate of neural discharge in the dorsal raphe, increase the rate of neural discharge in the ventral tegument air and the rate of discharge in the pyramidal cells of the hippocampus (CA1). In comparison, intravenous perfusion of clomipramine decreases the rate of neural discharge in the coeruleus locus, the dorsal raphe, the ventral tegument air (temporarily) and the pyramidal cells of the hippocampus. Iontophoretic application of tianeptine does not affect the response of pyramidal cells in the hippocampus to application of serotonin or gamma amino-butyric acid (GABA), but lowers recovery time after iontophoretic administration of serotonin or GABA. Iontophoretic application of clomipramine increases pyramidal cell response to serotonin but not to GABA and lengthens the recovery time after serotonin and GABA. The results are in agreement with the fact that tianeptine, unlike clomipramine, increases serotonin capture. Tianeptine leads to an original electrophysiologic pattern distinct from classic antidepressants and clomipramine.

[Influence of the administration of psychopharmacological compounds on the take up time of an alimentary material in the hamster and a study of the associated behaviour (author's transl)]. / Influence de l'administration de composés neurotropes sur le temps de ramassage d'un matériel alimentaire chez le hamster, et étude du comportement associé

The take up time of a standardized alimentary material is a simple component of hamster hoarding behaviour. This value was modified by administrations of the following compounds: diazepam, chlorpromazine, meprobamate, apomorphine, d-amphetamine, piribedil, fenfluramine, sulpiride, imipramine, phenobarbital, clonidine and morphine. The change consisted of a varying increase in the take up time, dependent upon the substance and dosage. High doses of chlorpromazine, apomorphine and fenfluramine inhibited the take up. A behavioural study connected with alimentary take up was included in the experiment. Some behavioural modifications (increase or decrease in motor activity, myorelaxation, stereotyped exploration, reciprocating movements) demonstrated differences between the studied compounds related to their pharmacological properties. The immediate consumption of food, without take up and hoarding behaviour, observed with meprobamate treatment, was an interesting and unexpected change in hamster behaviour. The measurement of the take up time and analysis of behavioural modifications may be useful in comparing and preliminary screening of new psychopharmacological compounds.

Pharmacological properties of (N-dicyclopropylmethyl) amino-2-oxazoline (S 3341), an alpha-2 adrenoceptor agonist.

Pharmacological actions of (N-dicyclopropylmethyl)-amino-2-oxazoline (S 3341), an agonist of alpha-2 adrenoceptors, were examined in acute animal studies. In the normotensive anaesthetized dog S 3341 (0.3 mg/kg, i.v.) produced an initial transient increase followed by a marked, prolonged fall in mean arterial pressure (MAP) of 20 mmHg. Central actions of S 3341 were demonstrated by administration of low doses into the vertebral artery of the anaesthetized dog. A rapid and marked fall in MAP resulted which was antagonised by piperoxan. Splanchnic discharges were strongly decreased following S 3341 i.v. administration, suggesting a centrally mediated diminution of sympathetic tone. Peripheral actions of S 3341 were observed in the pithed rat where a dose-dependent increase in MAP was noted which was somewhat antagonised by prazosin and largely by prazosin plus yohimbine. S 3341 reduced hypertension and tachycardia due to stimulation of the sympathetic outflow in the pithed rat, an effect also antagonised by piperoxan. These effects were more marked and prolonged than those of clonidine. S 3341 reduced the tachycardia resulting from stimulation of the cardioaccelerator nerve in the anaesthetized, spinalised and bilateraly vagotomised dog, this effect was reversed by piperoxan. S 3341 did no change the tachycardia induced by noradrenaline or tyramine. Plasma renin activity was significantly decreased after S 3341 treatment in dogs on low normal or high sodium diets. In rats S 3341 decreased the rate of discharge of noradrenergic cells located in the locus coeruleus which are believed to be involved in wake/sleep mechanisms. This depression was 63 times less than that of clonidine. At effective hypotensive doses S 3341 produced no sedation (i.e. loss of righting reflex) in 2 day old chicks. In addition the sedative action of clonidine was inhibited by S 3341 pretreatment. In the mouse tail flick model, the antinociceptive effects of S 3341 were 45 times less than those of clonidine. S 3341, an oxazoline derivative, appears to have haemodynamic effects similar to those of other agonists of central alpha-2 adrenoceptors but with fewer side-effects, and therefore could be of interest an as antihypertensive agent.

[New therapeutic indications for a dopamine antagonist, Piribedyl]. / Nouvelles indications thérapeutiques d'un agent agoniste dopaminergique: le piribédil.

Evidence has been found for the view that piribedil stimulates peripheral and central dopamine receptors. Piribedil stimulates the nigro-striatal pathway and has been shown to be an effective antiparkinsonian agent. The stimulation of dopamine receptors in the meso-limbic and/or meso-cortical pathways lead to propose its use in the treatment of affective disorders (maia and depression). Piribedil stimulates dopamine receptors located in the tubero-infundibular pathway and reduces the secretion of prolactine, producing ablactation ; it increases the secretion of STH. Recent studies suggest that the peripheral effects of piribedil, mainly the increases in femoral and cerebral blood flows are also due to stimulation of peripheral dopamine receptors.