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.

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.

Antagonism of hypothermia and behavioral response to apomorphine: a simple, rapid and discriminating test for screening antidepressants and neuroleptics.

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.

Oxolinic acid and diazepam: their reciprocal antagonism in rodents.

The stimulant effects of oxolinic acid were investigated in rats and mice. This drug, given orally, consistantly induced, in doses ranging from 16 to 256 mg.kg-1, locomotor stimulation and stereotyped behavior. These effects were antagonized by pimozide (1 mg.kg-1), alpha-methyltyrosine (64 mg.kg-1) or reserpine (4 mg.kg-1, 24 h before testing) pretreatment, suggesting a facilitatory role of oxolinic acid on catecholaminergic processes. Diazepam (4-16 mg.kg-1) reduced the stimulant effects induced by oxolinic acid but not those induced by amphetamine; oxolinic acid (8 mg.kg-1) markedly reduced the antipunishment effect elicited in rats by diazepam (2 mg.kg-1). Since benzodiazepines have been reported to enhance GABA functioning, these data suggest that oxolinic acid may impair GABA transmission. However, neither muscimol (0.5-1 mg.kg-1) or gamma-acetylenic-GABA (16-64 mg.kg-1) selectively reduced the stimulant effects elicited by oxolinic acid. Therefore, the possible facilitation exerted by this drug on catecholaminergic systems may not derive from the release of an inhibitory GABAergic control.

[Effects of four beta-blocking agents on some psychopharmacological tests in mice (author's transl)]. / Effets de quatre bloqueurs bêta-adrénergiques sur quelques tests de psychopharmacologie chez la souris.

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 themseleves in the same order of potency: penbutolol greater than propranolol greater than alprenolol greater than 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.

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.

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.

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.

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.

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.

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.

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.

Effects of drugs affecting the noradrenergic system on convulsions in the quaking mouse.

Handling-induced convulsions in the quaking mouse can be blocked by: phenobarbital, pentobarbital or phenytoin; postsynaptic alpha-adrenoceptor agonists (noradrenaline, phenylephrine, CRL 40028); presynaptic alpha-adrenoceptor blockers (yohimbine, mianserine); catecholamine liberating agent (amphetamine); noradrenaline reuptake inhibitors (cocaine, imipramine, desipramine). Moreover, the protective effect of yohimbine was antagonized by clonidine, prazosin or alpha-methylparatyrosine, and the protective effect of CRL 40028 was antagonized by prazosin but not by alpha-methyltyrosine. Drugs acting by other mechanisms (pilocarpine, atropine, trihexyphenidyl, (--)-5-HTP, methysergide, pimozide, clonidine, alpha-methyl DOPA, prazosin, isoprenaline, salbutamol) did not protect against convulsions. A slight protection was obtained with high doses of apomorphine and also with (+/-)-propranolol. This effect is probably not related to blockade of beta-adrenoceptors because the same effect was obtained with (+)propranolol. In young quaking mice, where susceptibility to convulsions is low, both postsynaptic alpha-adrenoceptor blockers and presynaptic alpha-adrenoceptor antagonist lowered the convulsive threshold. Thus, this seems to constitute an interesting model for the in vivo study of substances which affect the central alpha-adrenoceptors either pre- or postsynaptically.

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.

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.

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.

[Models of inhibition in animal behavior]. / Modèles d'inhibition du comportement chez l'animal.

The concept of inhibition in psychopharmacology is discussed by presenting different models of behavioral inhibition in animals. The inhibitions induced by fear or anxiety appear as a result of punishment introduction into an unknown situation, frustration... These inhibitions are particularly sensitive to minor tranquilizers. The inhibitions induced by "fatigue" appear when avoidance situations continue for 24 hours or when a situation demands a marked increase of animal activity to obtain the same reward (food). These inhibitions are particularly sensitive to psychoanaleptics. The inhibition induced by placing a animal in an inescapable situation is particularly sensitive to antidepressants.

[The new versus the old antidepressant drugs: a comparative study of their psychopharmacological profiles (author's transl)]. / Profils psychopharmacologiques des nouveaux antidépresseurs comparés aux antidépresseurs classiques.

We studied 13 known or potential antidepressants, choosen in different pharmacological classes: desipramine, imipramine, nialamide, dexamphetamine, AHR 1118, amineptine, iprindole, mianserine, nomifensine, salbutamol, TRH viloxazine, zimelidine. Each of these compounds was studied on 8 psychopharmacological tests: motor activity, reserpine induced hypothermia, reserpine induced ptosis, oxotremorine induced hypothermia, oxotremorine induced tremors, high doses apomorphine induced hypothermia, potentiation of toxic effects of yohimbine, behavioural despair. Clinical active compounds are efficient on yohimbine test and at least on one model of hypothermia; with a few exceptions, easy to explain, substances with a clearly demonstrated antidepressant activity in human have some common effects; these common effects can be used to predict, from animal experiments, an antidepressant effect in man.