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The social interaction test was used to examine the effects of an extract of Ginkgo biloba (EGb 761) and its possible interactions with diazepam and ethyl beta-carboline-3-carboxylate (beta-CCE). Pairs of naive (unfamiliar) male Wistar AF rats subjected to the same treatment were placed in a novel test arena that was brightly illuminated, and the duration (in s) of social contact was observed over a 10 min period. Single injections of EGb 761 (8-16 mg/kg, i.p.), given 30 min prior to testing, or repeated oral administration of the extract (48 or 96 mg/kg/day) for 8 days, significantly decreased social contact under conditions that did not influence locomotor activity. Injection of diazepam (1 mg/kg, i.p.), 30 min before testing, significantly increased social contact. Injection of diazepam to animals that had received repeated oral treatment with EGb 761 (96 mg/kg/ day) increased social interaction to an extent greater than observed with diazepam alone. Injection of beta-CCE (2-16 mg/kg, i.p.), 15 min before testing, significantly decreased social contact. When the animals were treated with EGb 761 (48 or 96 mg/kg/day, p.o. for 8 days) and beta-CCE (4 mg/kg), both of which decreased social interaction when administered alone, the resulting level of social contact was similar to that of control animals. Interactions with certain sites of central GABAA/ benzodiazepine/Cl- channel receptor complexes could be involved in mediating these effects of EGb 761, diazepam and beta-CCE.

Interesting psychotropic properties (psychostimulant, anti-depressant) were shown for a series of 3,4-diarylpiperidines. Optimization of these properties was obtained by Topliss method for determining the structure-activity relationship. Anti-depressant activity with little psychostimulant effect was observed in Mice and Rats with the trans 4-(4-trifluoromethylphenyl)-3-phenyl piperidine. Antihypertensive activity was not found among dopamine chained piperidines. Synthesis, relative configuration and conformation, pharmacologic study of 3,4-diarylpiperidines are described.

Resume Des proprietes psychotropes interessantes (psychostimulante, antidepressive) ont ete mises en evidence dans une serie de 3,4-diarylpiperidin-2-ones. L'optimisation de ces proprietes a ete obtenue par la methode de relations structure-activite elaboree par Topliss. Une activite antidepressive accompagnee d'un effet psychostimulant minime a ete observee sur la souris et le rat dans le cas de la 4-(4-chloro-3-trifluoromethylphenyl)-3-phenylpiperidin-2-one de configuration trans . Les syntheses des piperidin-2-ones et l'etude pharmacologique sont decrites, la determination de la configuration relative et de la conformation de ces composes a ete effectuee.

A mouse model of barbital-induced narcosis was used to examine the effects of single intraperitoneal injections of an extract of Ginkgo biloba (EGb 761), an extract devoid of terpene trilactones (CP 205), and three terpene trilactone constituents of the extract (ginkgolides A and B, bilobalide). Administration of sodium barbital (180 mg/kg, IP) to the mice caused narcosis, measured as a loss in righting reflex. Single injections of EGb 761 (25 and 50 mg/kg), given 60 min prior to sodium barbital, significantly shortened barbital-induced sleeping time, whereas these same doses of CP 205 were ineffective. Single injections of ginkgolide B (1 mg/kg) and bilobalide (2 and 5 mg/kg) significantly shortened sleeping time, whereas ginkgolide A was ineffective. The effects of ginkgolide B and bilobalide were reflected as increases in latency to onset of sleep and those of EGb 761, ginkgolide B, and bilobalide were correlated with decreases in the number of mice that slept. At the behavioral level, these potent in vivo effects of EGb 761, ginkgolide B, and bilobalide resemble those of certain antidepressants. At the molecular level, it is hypothesized that interactions with the picrotoxinin/TBPT site of GABA-regulated Cl− channels of the CNS may be involved. This information appears useful in explaining the clinically observed “vigilance-enhancing” and “antidepressant-like” actions of EGb 761.

We will present data from the comparison between four tests in mice of 10 1,4-benzodiazepines and one 1,5-benzodiazepine (clobazam). The tests used were: the "4 plates test" of anxiolytic activity; the electroshock test to determine the anticonvulsive effects; actimetry to predict the sedative effect on motricity; and traction test to predict the myorelaxant effect. The latter two tests have been suggested to be predictive of side-effects that damage psychomotor efficiency in human patients. A comparison of ED50s determined from the predictive tests of the therapeutic effect and those of the side-effects led to the calculation of ratios considered to be predictive of the safety margin. A classification according to this margin shows the advantages of the 1,5-benzodiazepine compared with the 1,4-benzodiazepines. Despite the caution needed in the extrapolation of the results from animals to humans, this work stresses the interesting place that the 1,5-benzodiazepine seem to hold as anticonvulsant in clinical practice.

Resume Dans une serie de nouvelles tetrahydropyrones-2, une activite psychostimulante depourvue d'activite anti-depressive est mise en evidence notamment dans le cas de la (methoxy-4 phenyl)-3 methyl-6 phenyl-4 tetrahydro-3,4,5,6 pyrone-2 de configuration relative (3 RS , 4 RS , 6 SR ). La configuration relative et la conformation des composes etudies sont determinees par RMN du proton et IR. La relation entre leur activite psychotrope et leur stereochimie est etudiee. Une activite psychostimulante depourvue d'activite anti-depressive est trouvee uniquement dans le cas des composes de configuration relative (3 RS , 4 RS , 6 SR ) qui adoptent une conformation demi-chaise.

In mice tested for 60 min in photometer-activity boxes, an increased locomotor activity (+50% to +100%) was observed after administration of cocaine (4 mg/kg i.p.). Such hyperactivity was markedly enhanced by all benzodiazepines studied (flurazepam excepted), at doses which did not modify spontaneous motility: chlordiazepoxide (1 mg/kg), diazepam (1 to 2 mg/kg), clobazam (1 mg/kg), oxazepam (0.25 mg/kg), nitrazepam (0.03 to 0.25 mg/kg), flunitrazepam (0.015 mg/kg), clonazepam (0.004 mg/kg) and lorazepam (0.004 mg/kg). These doses are very low, e.g., 8 to 20 times lower than those required to antagonize the locomotor stimulation caused by cocaine. The increase of cocaine-induced hypermotility elicited by nitrazepam (0.125 mg/kg i.p.) was reduced or suppressed by impairing gamma-aminobutyric acid (GABA)-ergic transmission with picrotoxin (0.25 mg/kg) or by blocking α or β adrenergic receptors with prazosin (1 mg/kg i.p.) or propranolol (4 mg/kg i.p.), respectively. At these doses neither picrotoxin, prazosin, nor propranolol modified the spontaneous locomotor activity or the hyperactivity induced by cocaine alone. These results suggest that benzodiazepines may exert their facilitatory activity on cocaine-induced hyperactivity by interfering with some central catecholaminergic processes either directly or through the involvement of a GABA-ergic link.

Common effects of four beta-adrenergic blocking drugs have been investigated in mice using classical and new psychopharmacological tests. Propranolol, alprenolol, practolol and penbutolol reduced the increase in locomotor activity produced by reserpine after MAO inhibition; they produce hypothermia when associated with amphetamine and they increase oxotremorine-induced hypothermia. Regarding these three tests the studied substances ranged themselves in the same order of potency: penbutolol > propranolol > alprenolol > practolol. Propranolol and penbutolol decreased the toxicity provoked in crowded mice by amphetamine or by the association pargyline-reserpine; alprenolol and practolol did not. Propranolol, penbutolol and alprenolol antagonized the amphetamine-induced increase in motor activity; practolol did not. When used at doses for which d-l propranolol was active, the dextrogyre isomer of propranolol was without effect whatever the test studied. It is suggested that for the selection of a beta-blocking drug, regarding central effects in man, the tests described would deserve consideration.

Summary In animal experiments and in man salbutamol has the profile of an antidepressant agent. In an attempt to determine if one of the experimental animal models used reflected a central effect of the drug, we compared the magnitude of the modifications obtained on four models after intraperitoneal (i.p.) or intra-cerebroventricular (i.c.v.) administration of salbutamol. We considered the effects of salbutamol in three models: the antagonism of the reserpine-induced hypothermia, of the apomorphine-induced hypothermia and the decrease in locomotor activity; the effects of the drug administered i.p. or i.c.v. were all the same in these systems. On the contrary, the antagonism of oxotremorine-induced hypothermia was stronger after i.c.v. administration of salbutamol or of isoproterenol; similarly, the potentiation of this hypothermia was stronger after i.c.v. administration of alprenolol than after i.p. administration. This test could become a useful model of a possibly central beta-adrenergic effect.

The effects of nine benzodiazepines on the locomotor stimulation induced in mice by cocaine (4 mg . kg-1 i.p.) were studied. These benzodiazepines markedly enhanced cocaine-induced hyperactivity. This effect was observed at low doses, e.g. doses at least 8 times lower than those required to depress the stimulation caused by cocaine. Nitrazepam-induced enhancement of the hyperactivity elicited by cocaine was reduced or suppressed by blocking dopaminergic receptors with pimozide (0.015--0.03 mg . kg-1), by interrupting GABAergic transmission with picrotoxin (0.25--0.5 mg . kg-1) or blocking alpha- or beta-adrenergic receptors with prazosin (0.25 mg . kg-1) or dl-propranolol (4 mg . kg-1) respectively. At these doses, neither pimozide, picrotoxin, prazosin nor propranolol were able to modify the spontaneous locomotor activity or the stimulation elicited by cocaine alone. Strychnine (0.25--0.50 mg . kg-1) or methysergide (2 mg . kg-1) failed to alter the enhancement by nitrazepam of cocaine-induced hyperactivity. These results suggest that an interaction of benzodiazepines with some catecholaminergic processes, either directly or through the involvement of a GABAergic link, may account for their facilitatory activity on cocaine-induced locomotor stimulation.

Pirlindole, a tetracyclic drug, is known to have a reversible and short-lived monoamineoxidase inhibitory activity. When administered after a supramaximal inhibitory dose of a classic monoamineoxidase inhibitor, pirlindole continues to antagonize reserpine-induced ptosis and oxotremorine-induced akinesia in mice. These results indicate that some central effects of pirlindole are partially independent of its monoamineoxidase inhibitor activity.

Male Wistar rats were trained to press a lever with food reinforcement according to a continuously reinforced schedule (CRF). Afterwards, rats were subjected to three experimental sessions (30 min each) during which responding was rewarded according to a progressive ratio schedule (following an initial 2-min CRF period, the number of presses necessary for the pellet delivery was doubled every second minute). Responding during the first half of each session, i.e., pressing for food, was maintained at a significant level, whereas it was almost suppressed during the second part of the session. As compared to controls (200 +/- 20 presses/30 min) animals given amfonelic acid (0.5, 1 mg/kg IP), methylphenidate (4, 8 mg/kg IP), caffeine (16 mg/kg IP), cocaine (4 mg/kg IP), oxolinic acid (32 mg/kg IP), nomifensine (4 mg/kg IP), DR 250 (2, 4 mg/kg IP) and d-amphetamine (0.25, 0.5, 1 mg/kg IP) showed an increased rate of responding ranging from 400 to 950 presses/30 min. In contrast, apomorphine, MK 486 + L-dopa, trihexyphenidyl, imipramine, salbutamol and diazepam did not increase responding. These results suggested that this test is highly sensitive for psychomotor stimulants and perhaps for their ability to enhance the reinforcing value of the reward or stimuli associated with the reward. Such activity seemed related to a catecholaminergic substrate since the increase of responding induced by amphetamine was blocked by pimozide, d,l-propranolol and prazosin.

The following behavioral modifications were observed after a single i.p. administration of T.R.H. (thyreo-tropin-releasing hormone) in mice or rats at doses higher than 4mg · kg−1: I. an increased reactivity to stimuli, II. periods of excitation alternating with periods of aggressivity, III. unusual movements (“tail-rattling” and “wet-dog”), IV. the reserpine- or oxotremorine-induced hypothermia was antagonized in mice by T.R.H. in doses of 1 mg · kg−1 and higher, but only a few other symptoms were influenced. The prochlorperazine-induced catalepsy in rats was antagonized by T.R.H.; under the experimental conditions, sudden hyperkinetic episodes were observed. The toxicity of pargyline-l-Dopa association was slightly increased, amphetamine- or apomorphine-induced stereotyped behavior was unchanged. This spectrum of activity is different from other known psychotropic drugs.

Yohimbine has a protective action on the convulsive seizures induced in quaking mice by tactile stimulation. In contrast, phentolamine, prazosine, and clonidine administered alone have no effect on the seizures. This effect of yohimbine is antagonized by prior administration of clonidine or prazosine. The anticonvulsivant effect of yohimbine is discussed in terms of its action on the presynaptic alpha-adrenergic receptors.

The antagonism of hypothermia induced by two doses of apomorphine (1 to 16 mg/kg) is proposed as an improved screening test for both neuroleptics and antidepressants. Low dose apomorphine-induced hypothermia (1 mg/kg) differentiates sulpiride-like neuroleptics (which better antagonize this effect of apomorphine than other effects such as stereotyped behavior) from haloperidol-like drugs. The latter equally antagonize the two effects of apomorphine. The effects of sulpiride are also distinct from those of chlorpromazine-like drugs which strongly antagonize stereotyped behavior, but not hypothermia induced by apomorphine. Hypothermia induced by a high dose of apomorphine (16 mg/kg) is not antagonized by neuroleptics, but is strongly antagonized by antidepressants (imipramine-like drugs, amineptine, amoxapine, nomifensine, viloxazine) and potential antidepressants (beta-adrenergic stimulants). The use of these two tests rapidly screens both antidepressants and neuroleptics and classifies neuroleptics according to their profile of action on the dopaminergic system.

Summary Bromocriptin and methylergometrine were studied with a battery of classical tests used in psychopharmacology. Both drugs have the typical profile of the dopaminergic stimulant drugs. Stereotyped behavior induced by both drugs were studied after various pharmacological pretreatments. Results of these interactions are in favor of a direct stimulation of dopaminergic receptors by both drugs. Since some characteristics of stereotyped behavior induced by bromocriptin are suppressed by methysergide but not by fenclonine, bromocriptin could also be a direct stimulant of serotoninergic receptors.

Behavioral and pharmacological tests were performed on rats (males Wistar A.F.) maintained either during 6 weeks at 20 or 5 in a cage (40×40×17 cm) or during 6 weeks at 20 and during 8 days at 5 in cage.

The influence of three beta-adrenergic blocking agents was studied on the stereotyped behavior induced in rats by a range of doses of d-amphetamine or apomorphine. The stereotyped behavior was assessed either clinically (quotation from 0 to 3 at various times for each rat) or using the confinement motor activity test. From 8 mg/kg (i.p.) onwards, propranolol and prinodolol clearly potentiated the amphetamine-induced stereotyped behavior without any modification of the apomorphine-induced stereotyped behavior. Practolol, known for its poor passage through the blood-brain barrier had only a slight effect.

1. SAL is a tetraisoquinolein (T.I.Q.), resulting from the condensation of acetaldehyde and dopamine. 2. SAL, injected intraperitoneally, is active in tests commonly used to screen potential antidepressants. 3. This effect is especially studied by using antagonism of apomorphine, reserpine, oxotremorine-induced hypothermia. 4. The noradrenergic system seems to be involved in the mechanism of action.

The effects of piracetam on the amnesias induced by scopolamine, diazepam and electroconvulsive shock (ECS) were studied in a passive avoidance procedure in the mouse and compared with the interactions of piracetam with the major behavioral effects of these treatments, namely scopolamine-induced hyperactivity, diazepam-induced release of punished behavior (Four Plates Test) and ECS-induced convulsions. Amnesia was induced by injecting scopolamine or diazepam (1 mg/kg, IP) 30 minutes before or applying ECS immediately after the first session (S1) of the passive avoidance task. Piracetam was studied at 3 doses (512, 1024 and 2048 mg/kg) administered PO 60 minutes before S1. Retention was measured 24 hours later (S2) in the absence of any treatment. Piracetam dose-dependently attenuated the memory deficits induced by the three amnesic treatments but did not affect either scopolamine-induced hyperactivity, diazepam-induced release of punished behavior or ECS-induced convulsions. These results point to the specificity of piracetam's anti-amnesic activity and, in particular, suggest that piracetam can suppress the memory disturbances induced by diazepam without affecting diazepam's anxiolytic activity. The test battery employed would therefore seem highly suitable for evaluating the potential nootropic activity of novel compounds.

A novel test procedure for antidepressants was designed in which a mouse is suspended by the tail from a lever, the movements of the animal being recorded. The total duration of the test (6 min) can be divided into periods of agitation and immobility. Several psychotropic drugs were studied: amphetamine, amitriptyline, atropine, desipramine, mianserin, nomifensine and viloxazine. Antidepressant drugs decrease the duration of immobility, as do psychostimulants and atropine. If coupled with measurement of locomotor activity in different conditions, the test can separate the locomotor stimulant doses from antidepressant doses. Diazepam increases the duration of immobility. The main advantages of this procedure are the use of a simple, objective test situation, the concordance of the results with the validated "behavioral despair" test from Porsolt and the sensitivity to a wide range of drug doses.

The effects of enantiomers of nomifensine were compared in five psychopharmacological tests in which (±)-nomifensine is active. In mice, (+)-nomifensine increased motor activity at 16 mg/kg, 8 mg/kg recuced the hypothermia and ptosis induced by reserpine and antagonized the hypothermia induced by 16 mg/kg of apomorphine. (+)-Nomifensine 4 mg/kg potentiated yohimbine toxicity. (−)-Nomifensine 4, 8 or 16 mg/kg was inactive in all these tests. In rats, (+)-nomifensine 8 mg/kg induced stereotyped movements whereas (−)-nomifensine 64 mg/kg did not produced dtereotypies.

Eleven benzodiazepines were evaluated in the staircase test in mice. The behavioural parameters measured were the number of steps climbed and the number of rears during a 3-min test. Climbing and to a lesser extent rears were enhanced at low doses, whereas both parameters, particularly rearing, were reduced at higher doses. The differential effects of the drugs on the two parameters were used to determine indices of anxiolytic efficacy for each drug where increases in climbing were taken to indicate the onset of anxiolytic activity and decreases in rearing the onset of sedative activity. The compounds could be ranked according to these indices in a manner which appears to reflect their therapeutic profile in man.

We studied the interactions between CRL 40028 (benzhydryl sulfinyl) acetohydroxamic acid) and the alpha 1 blocker prazosin, in mouse. CRL 40028 antagonizes prazosin-induced hypothermia and hypomotility; prazosin antagonizes the anticonvulsant effect of CRL 40028 in the quaking mouse.

Several studies have indicated that α -adrenergic systems are implicated in the anticonvulsant activity of diphenyl-hydantoin. We now report that in mice prazosin (0.125 mg/kg), a blocker of α 1 -adrenoceptors, reverses the effects exerted by diphenylhydantoin (256 mg/kg) in tests which are predictive of antidepressant activity: reserpine-induced ptosis and immobility which are caused by inescapable, aversive situations. These date indicate that α -adrenoceptors are not only involved in the anticonvulsant action of diphenylhydantoin, but also in its antidepressant-like effects.

The model proposed here assumes that depressive disorders could reflect an extreme state of a current behavioral strategy. According to this model, a subject facing a problem of survival without apparent solution may choose between two behavioral patterns: searching for a solution or waiting for that solution to occur. This choice can be made after one or several estimations of the cost and benefit attached to each of these alternatives. Two of the main behavioral models of depression are interpreted according to this model: namely, infant response to maternal separation in monkeys and "behavioral despair" in rodents. Practical and theoretical consequences of this model are discussed.

1. Mice when suspended by the tail will alternate between active attempts to escape and immobility. Immobility like that measured in the behavioral despair test is reduced by a wide variety of antidepressant agents. 2. The present paper describes a computerized version of this test (ITEMATIC-TST) which in addition to recording immobility measures the power of the movements. 3. Various tricyclic (amitriptyline, desipramine, imipramine), MAOI (clorgyline, moclobemide, nialamide, pargyline, toloxatone) and atypical antidepressants (bupropion, citalopram, indalpine, mianserin, nomifensine, viloxazine) were tested and compared with psychostimulants (d-amphetamine, caffeine), neuroleptics (chlorpromazine, haloperidol, sulpiride), anxiolytics (clobazam, diazepam) and agents acting on the cholinergic system (atropine, oxotremorine). 4. All antidepressants decreased the duration of immobility and most increased the power of movements. 5. The psychostimulants also decreased immobility but only amphetamine increased the power of movements. 6. Neuroleptics increased immobility without affecting the power of movements, whereas anxiolytics increased immobility but decreased the power of movements. 7. Atropine had a profile similar to antidepressants whereas oxotremorine tended to have opposite effects. 8. The results suggest that the automated test system with its two parameters is not only sensitive to antidepressants but could also be useful for generating activity profiles for different kinds of psychotropic agent.

In mice, pilocarpine - or oxotremorine - induced decrease in locomotor activity and increase of the reaction time to pain were antagonized by atropine and not by methylatropinium. Identical doses of atropine and methylatropinium suppressed the antagonism of the cholinergics towards reserpine-induced palpebral ptosis. Cholinergics-induced hypothermia was not clearly antagonized by atropine or methylatropinium.