[The atypical neuroleptic concept]. / Le concept de neuroleptique atypique.

Atypical neuroleptics can be defined as dopamine (DA) receptor blockers which differ from typical neuroleptics in that they have a markedly lower or absent propensity for the induction of parkinsonian side effects of tardive dyskinesias. Some of them, but not all, are also more effective in treating schizophrenic patients, i.e. those with negative symptoms or who resist to classical treatments. There may be four classes of potential atypical neuroleptics: 1) Antipsychotics such as sulpiride and remoxipride that block a subgroup of D2 receptors; 2) D1 antagonists that may prove to be a valuable new type of antipsychotic drug; 3) Partial D2 agonists and 4) Antipsychotics such as clozapine and risperidone which block DA as well as other receptors and which appear to have the most pronounced antipsychotic effect. The differences between typical and atypical neuroleptics may first relate to regional specificity in site of actions. Animal studies suggest that atypical neuroleptics may act preferentially on mesolimbic and mesocortical as opposed to striatal DA systems. Most studies which have attempted to define the biological mechanisms which subserve the differences between atypical and typical neuroleptic drugs have focused on receptor binding profile of these drugs. Relatively higher affinity for the serotonin (5HT2) receptor than for the D2 receptor may be important to the action of clozapine-like compounds. However, many other systems might be involved and it seems likely that the atypical neuroleptic profile could be achieved in more than one way.(ABSTRACT TRUNCATED AT 250 WORDS)

[Transcerebral electrostimulation in hypnotic drug withdrawal]. / Apport de l'électrostimulation transcérébrale dans le sevrage des hypnotiques.

This preliminary study attempted to test the efficacy of electrosleep therapy on hypnotic drug withdrawal. Among 89 outpatients complaining of chronic insomnia and receiving a heavy hypnotic drug treatment, an efficient withdrawal associated with a marked improvement of self-reported sleep was observed in 78% of cases, especially when insomnia was not related to medical aetiologies or to major psychiatric disorders. These results suggest further controlled studies to determine the magnitude of the placebo component in the effect observed.

Habituation of exploratory activity in mice: effects of combinations of piracetam and choline on memory processes.

The effects of various piracetam + choline combinations on an experimental model of memory were investigated. Mice were given two sessions in a simple photo-cell activity cage and the decrease in activity at the second session (habituation) served as an index of retention. Retention was facilitated by post-session administration of 2000 mg/kg piracetam IP and 50 mg/kg piracetam + 50 mg/kg choline IP. Similar injections of choline alone (10 to 200 mg/kg IP), piracetam alone (10 to 1000 mg/kg IP) or other combinations of piracetam and choline were without effect. These results, consistent with those reported elsewhere, suggest that piracetam can interact with choline to facilitate memory processes in mice.

Effects of imipramine on separation-induced vocalizations in young rhesus monkeys.

Three Rhesus monkeys were removed from their mothers at birth and reared together in a group cage. When they were one year old they were subjected to repeated separations during which they were placed alone for 1 hour in another cage in an acoustically isolated adjacent room. The number of vocalizations and gross body movements were recorded automatically. Single injections of imipramine (3.75, 7.5 and 15 mg/kg IM) instead of decreasing tended to increase the number of vocalizations without affecting motor activity. A similar pattern was observed when imipramine (3.75 and 7.5 mg/kg IM) was administered repeatedly (2 injections/day/4 days). The failure of imipramine to decrease separation-induced vocalizations in our conditions suggests that the procedure would not be useful for testing potential antidepressants.

Discrimination of the amphetamine cue. Effects of A, B and mixed type inhibitors of monoamine oxidase.

Rats were trained to discriminate between the effects of 0.6 mg/kg of (+)-amphetamine given intraperitoneally saline in a two-lever operant task, according to a fixed ratio ( FR10 ) schedule of food reinforcement. Once trained (greater than 90% responding on the appropriate lever during sessions with drug and saline, respectively over 2 weeks), they were given tests of generalization with various type A, type B or mixed type monoamine oxidase inhibitors (MAOI). Generalization was tested during the first 100 sec of a 15 min trial during which no reinforcements were given (extinction) followed by reinforcement on both levers for the rest of the session. Generalization to amphetamine was estimated using both the percentage of responding on the "drug lever" and a measure of choice of lever. None of the type A MAOI's tested [ cimoxatone (MD 780515), clorgyline, LY 51641, moclobemide (Ro 11-1163), toloxatone] showed generalization towards the lever for amphetamine. Clear or partial amphetamine-like responding was observed with the B type MAOI (+/-)-deprenyl and LY 54761 but not with two other type B MAOI's MD 240928 or pargyline. (+/-)-Tranylcypromine, but not nialamide (mixed type MAOI's), induced dose-dependent responding on the lever for amphetamine. It was concluded that amphetamine-like activity was not an intrinsic property of A or B type MAOI's.

Neuropharmacological profile of MD 790501, a new benzamide derivative.

Using several classical screening procedures in different species MD 790501: (exo)-2,3 dimethoxy-N-[8-(phenylmethyl)-8-azabiocyclo [3.2.1]oct-3-yl] benzamide hydrochloride was shown to possess potent neuroleptic properties. The doses effective in the tests for neuroleptic activity were similar to or lower than those for heloperidol and clearly lower than those for bromopride, chlorpromazine, sulpiridie, sultopride and thioridazine. Compared with the reference compounds tested MD 790501 showed sedative, cataleptic and dyskinetic effects at doses relatively higher than those effective in tests for neuroleptic activity. MD 790501 possessed no noradrenolytic, anticholinergic, proconvulsant or anxiolytic activity. Its acute toxicity was in the same dose range as that of reference neuroleptics.

Aortic occlusion by a balloon catheter: a method to induce hind limb rigidity in rats.

Post-ischaemic spinal extensor or flexor rigidity can be induced in different species by clamping or ligature of the descending aorta after thoracotomy or laparotomy. A similar motor deficit can also be induced by an intraluminal aortic occlusion produced by inflation of a balloon attached to the tip of a catheter inserted via the femoral artery. This method is easy to perform and avoids all the possible complications of thoracotomy or laparotomy. In rats the occlusion time for obtaining the maximum percentage of animals exhibiting a permanent hind limb extensor (62.5%) or flexor (12.5%) rigidity was 15-16 minutes. A marked depression of hind limb sensory perception accompanied this rigidity but there were no urinary, bowel or skin disturbances. The unilateral femoral ligation following the catheterization did not induce a difference in muscle tone between both hind limbs. The present procedure which is simpler than other published procedures might thus serve as a useful animal model for spastic paraplegia.

Antiapomorphine and locomotor effects of neuroleptics in rhesus monkeys.

Intramuscular injections of apomorphine (1 mg/kg) cause marked behavioral effects in rhesus monkeys including hyperactivity, repetitive stereotyped movements, chewing, tongue movements, licking, biting and vocalization. These effects occur within minutes of the injection and last 90-100 min. The antiapomorphine and locomotor depressant activity of chlorpromazine, haloperidol, MD 790501, sultopride and thioridazine, injected IM 1 hr before apomorphine, were assessed using a standardized rating procedure. All compounds antagonized the effects of apomorphine but differed in terms of potency and their relative effects on locomotor activity. The experimental compound MD 790501, a new benzamide derivative, was not only the most potent compound tested but, compared with its antagonism of apomorphine, caused the least marked depression of locomotor activity.

Neuropharmacological profile of MD 780515, a new reversible inhibitor of type A monoamine oxidase.

Using several classical screening procedures, MD 780515, 3-[[4-[5-(methoxymethyl)-2-oxo-3-oxazolidinyl]phenoxy]methyl]- benzonitrile, was shown to possess potential antidepressant activity consistent with preferential and short-acting inhibition of type A monoamine oxidase. The doses effective in the tests for antidepressant activity were much lower than the lethal doses and were similar to or lower than those for reference drugs. MD 780515 showed some anti-convulsant action but had little effect on spontaneous or conditioned behaviour and was devoid of anticholinergic activity.

Neuroleptic-induced acute dyskinesias in rhesus monkeys.

Rhesus monkeys, previously subjected to twice-weekly injections of various neuroleptics, subsequently respond to acute IM injections of haloperidol with marked bucco-lingual and whole body movement disturbances consisting of mouth opening, protrusion, retraction or curling of the tongue together with writhing movements of the neck, trunk and/or limbs. These phenomena, which closely resemble the acute dyskinetic or dystonic reactions described in patients at the beginning of neuroleptic treatment, were also observed after acute IM injections of other neuroleptics such as fluphenazine, metoclopramide, oxiperomide, sulpiride, sultopride and tiapride. No dyskinesias were observed after chlorpromazine, chlordiazepoxide, clozapine, RMI81582 or thioridazine at doses which otherwise had marked behavioural effects. The dyskinesias induced by haloperidol could be suppressed by prior treatment with the anti-cholinergic scopolamine. These observations, which correlate well with clinical findings, suggest that neuroleptic induced acute dyskinesias in the Rhesus monkey might be a useful model for predicting the liability of new anti-psychotics for inducing acute dyskinetic reactions in man.

Animal pharmacology of oxapadol (MD 720111), a new non-narcotic analgesic.

Oxapadol is a non-narcotic analgesic with an unusual chemical structure. It possesses analgesic activity in 4 species similar to that of other non-narcotic reference analgesics. It also shows antipyretic and antiinflammatory effects and in the analgesic dose range is devoid of undesirable neurological, gastro-intestinal and cardiovascular side-effects.

Forced swimming in rats: hypothermia, immobility and the effects of imipramine.

Rats when forced to swim in a restricted space not only became immobile but showed marked hypothermia. The hypothermia was greater than that observed after reserpine or Ro 4-1284 and was not antagonized by imipramine at doses which significantly reduced immobility. Hypothermia induced by forced swimming can therefore be dissociated from the immobility occurring in these conditions and also from drug-induced hypothermia.

Immobility induced by forced swimming in rats: effects of agents which modify central catecholamine and serotonin activity.

Rats were forced to swim in a restricted space will rapidly cease apparent attempts to escape and adopt a characteristic posture which we have termed "immobility". We show in previous experiments that immobility was reduced by a variety of antidepressant agents and thus suggested that the method could serve as a screening model for antidepressants. The present experiments showed that immobility was reduced by drugs which increase central dopaminergic and alpha-adrenergic activity but was less affected by drugs which act mainly on central serotonin. Conversely, immobility could be increased by drugs which diminish central catecholamine activity but not by drugs which inhibit central serotonin. It was concluded that immobility depended primarily on the activity of central catecholamines but that caution was required before ascribing immobility exclusively to activity within a single system.

"Behavioural despair" in rats and mice: strain differences and the effects of imipramine.

Rats and mice when forced to swim in a restricted space will rapidly cease attempts to escape and become immobile. Previous experiments have shown that immobility was selectively reduced by antidepressant agents. The present experiments show that important differences exist between strains in both the amount of immobility observed and the effects of imipramine. Strain differences should therefore be taken into account in attempts to replicate results from one laboratory to another.

Behavioural despair in rats: a new model sensitive to antidepressant treatments.

Rats when forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture which can be readily identified. Immobility was reduced by various clinically effective antidepressant drugs at doses which otherwise decreased spontaneous motor activity in an open field. Antidepressants could thus be distinguished from psychostimulants which decreased immobility at doses which increased general activity. Anxiolytic compounds did not affect immobility whereas major tranquilisers enhanced it. Immobility was also reduced by electroconvulsive shock, REM sleep deprivation and "enrichment" of the environment. It was concluded that immobility reflects a state of lowered mood in the rat which is selectively sensitive to antidepressant treatments. Positive findings with atypical antidepressant drugs such as iprindole and mianserin suggest that the method may be capable of discovering new antidepressants hitherto undetectable with classical pharmacological tests.

Behavioral despair in mice: a primary screening test for antidepressants.

A depressed state can be induced in mice by forcing them to swim in a narrow cylinder from which they cannot escape. After a brief period of vigorous activity the mice adopt a characteristic immobile posture which is readily identifiable. Immobility was reduced by tricyclic antidepressants, monoamine oxidase inhibitors and atypical antidepressants, as well as by electroconvulsive shock. Psychostimulants also reduced immobility but in contrast to antidepressants caused marked motor stimulation. Immobility was not affected by minor or major tranquilisers. These findings, closely parallel to those we have previously reported in rats, suggest that the procedure is selectively sensitive to antidepressant treatments. The mouse procedure is, however, more rapid and less costly than that with rats and is thus more suitable for the primary screening of antidepressant drugs.

[Alerting effect of vincamine in rats (author's transl)]. / Action éveiliante de la vincamine chez le rat.

The alerting effect of vincamine, an indole alkaloid of Vinca minor, has been demonstrated using three electropharmacological tests: 1) the sleep-wakefulness cycle of freely moving rats implanted with cortical electrodes, 2) the sleep induced by 200 mg/kg i.v. sodium 4-hydroxy-butyrate (GHB) in the curarized rat, 3) the duration of spindle activity in the E.E.G. of curarized rats provoked by an acute asphyxia in which the E.E.G. activity was abolished for 20 sec. Vincamine increased the total duration of wakefulness at the expense of sleep, decreased the number of phases of paradoxical sleep (PS), increased the latency of the first phase of PS, but had no effects on the sleep-wakefulness cycle in a further test 24 hours after administration. Vincamine induced neither stereotyped behavior nor hypermotility. Vincamine also decreased the duration of GHB-induced sleep and the duration of post-asphyxic spindles. All effects observed were dose dependent. By means of these electropharmacological tests we have been able to discover two further agents which have more potent alerting effects than vincamine: desoxyvincaminamide and N-cyclopropyl-desoxyvincaminamide.

Drugs and PGO waves in the lateral geniculate body of the curarized cat. V. Miscellaneous compounds. Synopsis of the role of central neurotransmitters on PGO wave activity.

In the last part of this series we have studied the effects of various drugs on ponto-geniculo-occipital (PGO) waves induced by the benzoquinolizine derivative, Ro 4-1284 (PGO(1284)), and by the inhibitor of trypotophan hydroxylase, p-chlorophenylalanine (PGO(PCPA)), and continuously recorder and counted in the lateral geniculate bodies (LGB) of unanaesthetized and immobilizedcats. The major aim of this study was to test the specificity of drug-induced alterations of the PGO wave activity suggested by the previous investigations. Hypnotics-sedatives of different classes had no significant effects in doses that did not markedly alter the electrical background activity in the LGB. A notable exception was gamma-hydroxybutyric acid which increased the density of PGO(1284) and PGO(PCPA). A number of neuroleptics were found inactive; sulpiride surprisingly decreased the density of PGO(1284). Bulbocapnine had a similar effect. Convulsants in subconvulsive doses did not uniformly affect PGO waves; while pentetrazole had no consistent effect, strychnine decreased and picrotoxin increased the density of PGO(1284). High doses of morphine, methadone and meperidine decreased the PGO(1284). Ethanol was inactive even in high doses. Caffeine and mefexamide reduced the density of PGO(1284). Mepiprazol was the most potent depressant of PGO(1284, probably by inhibiting the uptake of 5-HT. Mescaline was a weak depressor of PGO(1284). p-Chloromethamphetamine induced PGO waves in untreated cats less consitently than did PCPA. Amantadine reduced the amplitude of PGO waves due to a central antinicotinic action. The results of this study and of the whole series suggested a tentative scheme of the generation and modulation of PGO waves, in which the hypothetical roles and sites of action of four central neurotransmitters are included.

Drugs and PGO waves in the lateral geniculate body of the curarized cat. II. PGO wave activity and brain 5-hydroxytryptamine.

Ponto-geniculo-occipital (PCO) waves induced either by the benzoquinolizine derivative, Ro 4-1284 (=PGO(CPA), were continuously recorded and counted in the lateral geniculate bodies of unanaesthetized immobilized cats as described in the preceding communication. The effect of various drugs interacting with central 5-hydroxytryptaminergic mechanisms on the density (number hr(-1) or number 0.5 hr(-1) of PGO waves was investigated. The density of PGO waves was dose-dependently decreased and the waves were eventually abolished by the precursors of 5-hydroxytryptamine (5-HT), L-tryptophan and 5-hydroxytryptophan. 5-HT itself, injected intracerebroventricularly, tended to diminish the density. Lysergic acid diethylamide (LSD) was an extremely potent depressor of PGO(1284) and PGO(PCPA); psilocybine was almost as potent as LSD, whereas higher doses of N,N-dimethyltryptamine, bufotenine and yohimbine were required for the reduction of PGO waves. A number of tricyclic antidepressants reduced the density of PGO waves, their order of potency corresponding to that reported for their inhibitory effect on the uptake of 5-HT; tertiary amines were more potent than secondary amines. Desipramine was more potent on PGO(PCPA) THAN ON PGO(1284). Two dibenzothiepine antipsychotics, methiothepin and octoclothepin, increased the density of PGO(1284) and PGO(PCPA) and also induced PGO waves in untreated cats; the evidence suggests that these two compounds antagonize the effect of endogenous 5-HT in the brain. These results confirm some earlier findings and augment the pharmacological pieces of evidence for the stron inhibitory influence of 5-HT neurones on the generation ofPGO waves.