Effects of single intraperitoneal injections of an extract of Ginkgo biloba (EGb 761) and its terpene trilactone constituents on barbital-induced narcosis in the mouse.

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.

Interactions of Ginkgo biloba extract (EGb 761), diazepam and ethyl beta-carboline-3-carboxylate on social behavior of the rat.

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.

Microtubule disruption and cognitive defects: effect of colchicine on learning behavior in rats.

Neuropathological findings in Alzheimer's disease (AD) suggest a possible involvement of microtubule dysfunction in neurodegenerative process pathogenesis. Because microtubules have a major role in neuronal plasticity, microtubule disruption could be also directly responsible for cognitive defects in AD. We report that in rats, continuous microtubule disruption induced by chronic colchicine administration results in a dose-dependent learning deficit. In addition, retention is also impaired. These cognitive defects are specific, as chronic colchicine induces no other behavioral toxicity within the study dose range. Colchicine-induced cognitive defects resemble those of AD, which are characterised by amnesia of recent learning and loss of formerly established memories. This new procedure of pharmacologically induced cognitive impairment may prove useful, both towards understanding AD pathogenesis and towards drug screening.

Specificity of piracetam's anti-amnesic activity in three models of amnesia in the mouse.

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.

Use of the automated tail suspension test for the primary screening of psychotropic agents.

Mice, when suspended by the tail, will alternate between active attempts to escape and immobility. A specially developed computerized device (ITEMATIC-TST) automatically measures the duration of immobility of 6 mice at one time and at the same time provides a measure of the energy expended by each animal, the power of the movements. Use of these 2 parameters enables activity profiles to be generated which can distinguish different classes of psychotropic activity. Immobility is decreased by antidepressants and psychostimulants, but increased by neuroleptics and minor tranquillizers. Minor tranquillizers can be distinguished from neuroleptics in that they decrease the power of the movements, whereas neuroleptics are without effect on this parameter. The present experiments were undertaken to see whether the activity profiles generated in this procedure could indeed be useful for primary psychotropic screening. Eighteen compounds, including antidepressants, neuroleptics, minor tranquillizers, sedative/hypnotics, dopaminergic stimulants and 3 dummy compounds were first submitted to a shortened primary observation procedure for dose finding and were then investigated at 2 doses in the automated tail suspension test. All experiments were conducted blind. The results obtained largely confirm the activity profiles already reported in this test and show that the combined use of primary observation and the automated tail suspension test permit the unambiguous identification of the pharmacological activity of 15 of the compounds tested with tentative identification of the 3 remaining compounds.

The automated Tail Suspension Test: a computerized device which differentiates psychotropic drugs.

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.

Comparing benzodiazepines using the staircase test in mice.

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.

Adaptation of the tail suspension test to the rat.

In the tail suspension test (TST), the rat is suspended by the tail for 6 min during which the animal shows periods of agitation and immobility. The duration of the immobility is measured. Desipramine decreased the duration of immobility. The main advantages of this procedure are: the use of a simple, objective test situation; the concordance of the results (for desipramine) with the "behavioral despair" test described by Porsolt; the avoidance of the hypothermia induced by immersion in the Porsolt test.

Comparative study in mice of ten 1,4-benzodiazepines and of clobazam: anticonvulsant, anxiolytic, sedative, and myorelaxant effects.

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.

Antidepressant-like effects of diphenylhydantoin in mice: involvement of alpha-adrenoceptors.

Several studies have indicated that alpha-adrenergic systems are implicated in the anticonvulsant activity of diphenylhydantoin. We now report that in mice prazosin (0.125 mg/kg), a blocker of alpha 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 alpha-adrenoceptors are not only involved in the anticonvulsant action of diphenylhydantoin, but also in its antidepressant-like effects.

Psychopharmacological profile of salsolinol.

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

Psychopharmacological effects of nomifensine enantiomers.

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 reduced 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 produce stereotypies.

The tail suspension test: a new method for screening antidepressants in mice.

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.

[Differences in the mechanisms of the stimulant and antidepressive effects of nomifensine]. / Différence dans le mécanisme des effets stimulants et antidépresseurs de la nomifensine.

Four effects of nomifensine were studied in interaction with a dopamine receptor blocker (pimozide) and a beta-adrenergic receptor blocker (propranolol). The effects of nomifensine were divided into two categories: 1. Psychomotor stimulant effect a) Stimulation of locomotor activity in mice b) Stereotyped behavior in rats 2. Antidepressant effect a) Antagonism of hypothermia caused by reserpine in mice b) Potentiation of yohimbine-induced toxicity in mice. The psychomotor stimulant effects were antagonized by pimozide but not by propranolol. The antidepressant effects were antagonized by propranolol but not by pimozide. Our results support the hypothesis that nomifensine acts via both dopaminergic and noradrenergic mechanisms subserving distinct behavioral effects, psychomotor stimulant and antidepressant, respectively.

Searching-waiting strategy: a candidate for an evolutionary model of depression?

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.

Pharmacological evidence of the stimulation of central alpha-adrenergic receptors.

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.

The value of the reserpine test in psychopharmacology.

Numerous tests have been proposed to search for a possible antidepressive action. Many of these tests are based on a reversal of different reserpine effects, an approach justified mainly by the use of most the classic or new antidepressants. Three effects of reserpine were examined in mice: hypothermia, ptosis and akinesia. All tests were performed with reserpine 2.5 mg/kg, and the drugs were injected 4 h after reserpine administration. In these three models, we studied the relatively specific effects of 21 drugs known for their influence on the metabolism or action of norepinephrine (noradrenaline), serotonin and dopamine. Our results suggest that hypothermia antagonism is only obtained with drugs stimulating beta-adrenergic receptors directly or indirectly, ptosis antagonism with those stimulating alpha-adrenergic or serotonergic receptors, and akinesia antagonism with those stimulating dopaminergic receptors.

The progressive ratio schedule as a model for studying the psychomotor stimulant activity of drugs in the rat.

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.

[Unexpected interactions of some psychotropic drugs with barbital and pentobarbital effects in mice (author's transl)]. / Interactions imprévues de divers psychotropes avec les effets du barbital et du pentobarbital chez la souris.

Some of the substances studied modified the effects of the two barbiturates as expected and in the same direction: --chlorpromazine and diazepam increased the effects; --amphetamine and caffeine decreased them. Barbital, unlike pentobarbital, undergoes almost no metabolic transformation. This explains why pentobarbital is potentiated in the presence of proadifen, an inhibitor of liver microsomial enzymes, whereas the effect of barbital is unchanged, and probably explains similar results obtained with iproniazide and imipramine. For the same reason, rifampicine, an enzyme inducer, antagonizes the effect of pentobarbital without affecting that of barbital. The dissociated effects obtained with other substances are more difficult to explain: --increased effects of barbital without modification of the effects of pentobarbital (sulpiride); --decreased effects of barbital without modification of the effects of pentobarbital (methylphenidate, nomifensine, amineptine, oxolinic acid, methysergide); --decreased effects of barbital with increased effects of pentobarbital (viloxazine). Two hypotheses may be considered: 1. The study of barbital and pentobarbital concentrations in blood and brain would allow to exclude a pharmacokinetic interaction; 2. Barbital does not act through the same mechanism as pentobarbital.

Enhancement of cocaine-induced hyperactivity in mice by benzodiazepines: evidence for an interaction of GABAergic processes with catecholaminergic neurons?

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.