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The sleep of the baboon, Papio papio, under natural conditions and in the laboratory.

The sleep pattern of sixteen baboons (Papio papio) was studied under two very different conditions: (1) in a laboratory at Marseilles, the monkey being immobilized in a restraining chair in a soundproof cubicle; (2) in an African reserve, the monkey being housed in a large cage placed in its natural environment. Some very marked differences emerged. Sleep in the laboratory was longer (by 24 min) and richer in stage 3 and paradoxical sleep. In Africa, however, the sleep showed much more stage 1, was more fragmented and stages 2 and 3 and paradoxical sleep episodes were of shorter duration. Records made in Africa indicate that sleep is independent of slight environmental changes (day length, brightness of the moon, variations in temperature, calls of predators). But the comparison of the two series of results reveals the reorganization which occurs when the monkey is exposed to such different conditions. This adaptation to the environment affects, unequally, the various slow sleep stages and paradoxical sleep. In fact, the major modifications occur in stages 1 and 3 of slow sleep and in paradoxical sleep, while stage 2 appears to constitute the stable, unmodifiable nucleus of sleep.

Animals↗

[An electrophysiological study of direct occipito-frontal connections in centrum semi-ovale of Papio papio].

1. Evoked responses to single visual stimuli (VEP) and driving by intermittent light stimulation (ILS) were recorded with macroelectrodes from the central white matter (centrum semiovale) of 12 Papio papio baboons. 2. Two types of VEP were identified: VEPs with constant morphology, localized in the long associative bundles connecting the occipital, temporal and frontal lobes; VEPs with variable morphology and without any preferential localization; these probably originate from other types of fibres also belonging to the centrum semi-ovale. 3. Concerning the long associative bundles which have been individualized, they might be the equivalent of the occipito-frontal and the superior and inferior longitudinal bundles well known in man. The fusion frequency observed in these bundles during ILS increases from the frontal to the occipital lobe, because of their involvement (particularly in the parieto-temporal region) with other fibres of the centrum semi-ovale also likely to be driven by ILS. The existence of driving by ILS in these bundles demonstrates an activation of the frontal lobe by visual impulses.

Animals↗

[Action of ketamine of paroxysmal discharges provoked by air emboli in the baboon Papio papio].

Ketamine was administered to 18 baboons (Papio papio) to disrupt epileptic discharges elicited through intracarotid air injection. Discharge suppression was obtained in all animals but could be preceded by a phase of enhancement of the epileptic patterns, which rendered necessary the injection of a supplementary dose. The mechanisms of Ketamine action are discussed, in connection with data from the literature. Some of the latter suggest that its use in proved epileptics facilitates paroxystic patterns or even convulsions while others emphasize its antiepileptic action. Present data corroborate the ambivalent action of this drug. However, its dominant depressant effect obtained with increasing doses is somewhat favourable to its administration to epileptic patients.

Animals↗

Effects of melatonin on the photosensitive epilepsy of the baboon, Papio papio.

The acute pharmacological effects of melatonin (5-methoxy-N-acetyl-tryptamine) were evaluated on behaviour and electrographic signs in the photosensitive baboon (Papio papio), including visually evoked potentials VEPs). Doses of 5 and 10 mg/kg i.v. had little effect, contrasting with the enhancement of spontaneous paroxysmal activity and latency of clinical signs elicited by intermittent light stimulation (ILS) produced by the 20 and 50 mg/kg doses. Moreover, a modification of the electrographic pattern of discharge during ILS-induced myoclonic responses was observed. These observations indicate a slight decrease of light sensitivity after melatonin. Only frontal VEPs were modified, with increase in amplitude of their late components for all doses tested. These effects lasted for 2-4 h. The participation of serotoninergic mechanisms involved in melatonin effect and in this model of experimental epilepsy are discussed.

Animals↗

Proconvulsant, convulsant and other actions of the D- and L-stereoisomers of allylglycine in the photosensitive baboon, Papio papio.

The effects of the intravenous or intracerebroventricular injection of the stereoisomers, and the racemic mixture, of allylglycine (2-amino-pent-4-enoic acid) have been studied in baboons, Papio papio, with photosensitive epilepsy. Enhancement of the natural syndrome of photosensitivy epilepsy is seen 1-12 h (maximally at 3-8 h) after L-allyglycine, 100 mg/kg, intravenously, or D,L-allyglycine, 200 mg/kg, intravenously. Such enhancement is seen with a slower onset, and to a lesser, and more variable, extent after D-allyglycine, 500-750 mg/kg, intravenously. Brief focal or generalised seizures occurred (in the absence of intermittent photic stimulation) after L-allyglycine, 150-200 mg/kg, intravenously. This effect is similar to that previously observed after D,L-allyglycine, 300-400 mg/kg. D-Allyglycine, 780 mg/kg, intravenously produced episodes of vertical nystagmus with increased extensor motor tone, but no 'spontaneous' seizures. Intracerebroventricular injection of L-allylglycine, D-allyglycine or D,L-allyglycine, 100 mg in 1 ml saline, did not modify the natural syndrome of photosensitive epilepsy. D-Allylglycine, or D,L-allyglycine, 100 mg intracerebroventricularly, after 1-2 h gave rise to a syndrome with vomiting, sustained vertical nystagmus, and intermittent extensor spasms. The results are interpreted in terms of regional differences in the metabolism of the two isomers to active compounds that can inhibit glutamic acid decarboxylase. D-Allylglycine is active only at the brain stem and cerebellum because D-amino acid oxidase is largely confined to these brain areas.

Allylglycine↗

EEG and anticonvulsant effects of dipropylacetic acid and dipropylacetamide in the baboon Papio papio.

The ability of dipropylacetic acid (DPA) and dipropylacetamide (DPM) to modify EEG and seizure activity was assessed in 4 female and 3 male Papio papio. Doses of 30-60 mg/kg of DPA given at intervals over an 8 h period produced blood levels of 19-44 micrograms/ml which were not protective against intermittent light stimulation (ILS). Administration of 150-200 mg/kg doses at intervals over a 36 h period produced blood levels greater than 150 micrograms/ml and were highly protective against ILS. Similar results were obtained following adminstration of DPM; however, DPM appeared to offer greater protection against ILS. A moderate amount of seizure control was obtained at blood levels of 60-91 micrograms/ml (DPA) and complete blockade occurred at levels greater than 100 micrograms/ml DPA. Background EEG changes were similar following either DPA or DPM and consisted of a striking increase in total spectral power with relative power changes in 10-20 c/sec range, the magnitude of which was related to blood levels of DPA. Both agents produced a quieting effect on behavior without severe depression.

Animals↗

Characteristics and origin of frontal paroxysmal responses induced by light stimulation in the Papio papio under allylglycine.

In the Papio papio, curarized and rendered photosensitive by injection of a subconvulsant dose of DL-allylglycine, single flashes induce frontal paroxysmal evoked responses on condition that they be preceded by trains of intermittent light stimulation (ILS). The characteristics of these responses have been compared to those of non-paroxysmal responses induced in the same cortical area by isolated flashes (not preceded by trains of ILS). The paroxysmal responses resemble spikes and waves and consist of one or two positive spikes followed by a slow negative wave. The intracortical distribution of these responses has been studied in the motor cortex. The non-paroxysmal responses are probably not generated at this level. On the other hand, observations made during paroxysmal responses show the existence of two cortical responses; this demonstration follows from the existence of an inversion in some response components, linked to a negativity and a local cellular activation. A generator, situated in the pyramidal cell layer, is active during the positive surface spikes; the other generator, situated in the more superficial cortical layers, is active at the beginning of the slow negative surface wave. The cortical and subcortical afferents likely to bring these generators into play are discussed.

Afferent Pathways↗

Limbic status epilepticus: behaviour and sleep alterations after intra-amygdaloid kainic acid microinjections in Papio Papio baboons.

Limbic status epilepticus was produced with single microinjections of kainic acid in the amygdala of baboons (Papio papio). Long-term studies of the behavioural, electrographic and sleep alterations were performed. During status epilepticus the animals did not display aggressive behaviour. Feeding behaviour was diminished. Sleep was also deeply disturbed. Wakefulness was greatly increased, light slow wave sleep was diminished and deep slow wave sleep and paradoxical sleep was abolished. Sleep alterations persisted throughout the duration of status epilepticus (48-72 h). A modulation of paroxysmal discharges was observed depending on the degree of epileptogenicity of the limbic focus. Increased wakefulness cannot be attributed to convulsions since limbic status epilepticus in baboons is not accompanied by positive motor signs. It is proposed that increased wakefulness, of, a particular type as revealed by the alterations of different accompanying behaviours, during this type of status epilepticus, depends on an internal arousing mechanism.

Aggression↗

Transcallosal response (TCR) in the chronic photosensitive baboon preparation, Papio papio. I. Premotor cortical stimulation, recovery cycle and neurotropic drug effect.

Transcallosal response (TCR) and its recovery cycle were studied in the chronic photosensitive baboon, Papio papio. Bipolar premotor intracortical stimulation evoked early positive (P1) and negative (N1) sequences followed by late small positivity (P2) and large negativity (N2) in the contralateral homotopic site. The sequential pattern of P1 and N1 was similar to that previously described in acute preparations. The recovery cycle as measured by means of paired stimuli with varying inter-stimulus intervals (ISI) showed a marked supernormality of P1 and N1 at an ISI of 15-200 msec with maximal facilitation up to 250-300% of the conditioning response at an ISI of 30-50 msec. Pentobarbital (10 mg/kg) suppressed this supernormality without causing a constant TCR amplitude change. In contrast, a significant increase in both the TCR amplitude and the supernormality of the recovery cycle was observed with a subconvulsive dose (3 mg/kg) of Megimide, a presumed antagonist of pentobarbital. Our results suggest that (a) the recovery cycle is a more sensitive measure than amplitude for assessing the effect of neurotropic drugs on TCR, and (b) the P1, N1 amplitudes and the supernormality may represent different neuronal processes involved in the TCR.

Animals↗

Transcallosal response (TCR) in the chronic photosensitive baboon preparation, Papio papio. II. Effect of premotor cortical kindling.

The chronological pattern of transcallosal response (TCR) and its recovery cycle were studied by single or paired stimulation of the homotopic primary and the secondary (contralateral) cortical site before, during and after primary site premotor cortical kindling in Papio papio. Prior to kindling, the sequential pattern of TCR was early positive (P1), negative (N1), late small positive (P2) and large negative (N2) components. The recovery cycle of both P1 and N1 showed a marked supernormal phase at an inter-stimulus interval of 15-200 msec with a peak at about 30 msec, showing maximal facilitation up to 300%. Kindling, with or without prior low frequency cortical stimulation, resulted in a long-lasting amplitude potentiation of both P1 and N1 and a significant modification of the late components. However, a transient amplitude reduction was noted immediately following completion of stage 5 kindling, presumably due to repeated generalized convulsions. These changes occurred only during primary (kindling), but not secondary, homotopic site stimulation. These findings suggest that a persistently increased callosal transmission is probably due to primary site kindling-induced functional alteration of the synaptic site at the homotopic secondary site cortex. In contrast, the supernormal phase of the TCR recovery cycle was suppressed significantly at the secondary site cortex. Since a similar suppressive effect was observed with a small dose of pentobarbital in naive baboons, kindling is considered to produce enhancement of the inhibitory mechanism. However, a diminished suppressive effect on the supernormality 20 days after the termination of kindling suggests that this suppressive effect is transient. It is probably related to the repeated kindled convulsive seizures rather than to the kindling process itself.

Animals↗

Drugs modifying dopaminergic activity and behaviour, the EEG and epilepsy in Papio papio.

Acute changes in spontaneous motor activity, the EEG and photically induced epileptic responses have been observed in baboons (Papio papio) following the i.v. injection of drugs acting on dopaminergic transmission. Apomorphine hydrochloride, 0.5-1.0 mg/kg, produced a phase of acute excitement with accentuated vigilance and abnormal buccal motor activity lasting 30-40 min; during this phase myoclonic responses to intermittent photic stimulation were absent. After piribedil (ET 495, 1,2'' -pyrimidyl-4-piperonylpiperazine), 2-10 mg/kg, acute excitement was not seen. Intermittent delta activity was prominent in the EEG for 1-3 hr, and was associated with a slight reduction in photically induced epileptic responses. Haloperidol 0.6-1.2 mg/kg, produced a long-lasting reduction in spontaneous motor activity with an increased incidence of spontaneous EEG spikes and waves and a great enhancement of paroxysmal EEG activity during photic stimulation. Pimozide, 0.5-2.5 mg/kg, normally produced mild sedation and some EEG slowing. 2 animals responded idiosyncratically to both haloperidol and pimozide, displaying intermittent dystonic episodes with bucco-facial dyskinesia. These findings suggest that activation of dopaminergic receptors can lead to a reduction in myoclonic responses to photic stimulation.

Allyl Compounds↗

Anticonvulsant action in the photosensitive baboon, Papio papio, of a novel beta-carboline derivative, ZK 91296.

The anticonvulsant action of ethyl-5-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate (ZK 91296) has been studied in Senegalese baboons, Papio papio, with photosensitive epilepsy. Myoclonic and paroxysmal electroencephalographic responses to stroboscopic stimulation are diminished or abolished for 2-4 h after ZK 91296, 0.25-4 mg/kg, i.v. Radioreceptor assay of plasma ZK 91296 indicates rapid clearance (t 1/2 alpha, 5-20 min and beta, 60-90 min). In this model of generalised epilepsy ZK 91296 is similar to diazepam in potency but has a longer duration of action.

Animals↗

Action of suriclone in naturally and allyglycine-induced photosensitive baboons, Papio papio.

Suriclone (SC) is a new anxiolytic compound with a chemical structure different from that of benzodiazepines (BZD) but SC possesses a high affinity for the so-called BZD receptors. SC was tested in the naturally or the allylglycine-treated photosensitive baboon Papio papio. As active BZD administered by the intramuscular or oral route, this new compound possesses a marked protective effect against the excessive photosensitivity of the baboons, it blocks myoclonus following EEG spike and waves discharges induced by intermittent light stimulation; as BZD again, SC can induce spontaneous myoclonus not accompanied by EEG spike and wave discharges.

Administration, Oral↗

Stimulus-sensitive myoclonus of the baboon Papio papio: pharmacological studies reveal interactions between benzodiazepines and the central cholinergic system.

The baboon Papio papio develops a nonepileptic myoclonus 20 to 30 min after i.m. benzodiazepine injection. It is characterized by bilateral jerks involving mainly the neck and the trunk, by the absence of any correlative EEG paroxysmal discharge, and by its facilitation during movement or agitation. This myoclonus resembles the intention myoclonus of human patients as seen, for example, after anoxia. We found in experiments on 10 adolescent baboons that atropine alone induced the myoclonus for several hours, that physostigmine completely antagonized the benzodiazepine-induced as well as the atropine-induced myoclonus, and that the peripherally acting cholinergic antagonist, methyl-QNB, and agonist prostigmine had no action on the myoclonus, suggesting that the benzodiazepine-induced myoclonus in this species depends on a strong depression of the central cholinergic system by benzodiazepine. The benzodiazepine-induced myoclonus was mediated by benzodiazepine receptors as it was blocked by the specific benzodiazepine receptor antagonist, Ro 15-1788, which did not block atropine-induced myoclonus; latency to myoclonus after benzodiazepine was longer than after atropine. These facts suggest that benzodiazepines, by an as yet unknown mechanism, induce a depression of the cholinergic system which in turn leads to the development of myoclonus. Finally, the benzodiazepine-induced myoclonus of the baboon can be considered as a good model for testing drugs that act on the muscarinic cholinergic system and also for testing benzodiazepine-acetylcholine interactions.

Animals↗

Anticonvulsant actions of DS 103-282. Pharmacological studies in rodents and the baboon, Papio papio.

The anticonvulsant actions of DS 103-282 [5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3- benzothiadazole , tizanidine], have been evaluated after intraperitoneal administration in DBA/2 mice (seizures induced by sound), in Swiss S mice (seizures induced by N-methyl-D,L-aspartate; NMDLA ) and following intravenous or oral administration in Papio papio (seizure responses to intermittent photic stimulation). Protection against sound-induced seizures occurred after intraperitoneal administration of DS 103-282 (0.66-3.33 mg/kg). The ED50 doses for suppression of the tonic, clonic and wild-running phases of sound-induced seizures were 0.53, 0.79 and 1.3 mg/kg respectively. This protective effect of DS 103-282 (1.5 mg/kg, i.p.) was maximal after 30 min and was maintained for 60-120 min. Seizures induced by NMDLA were not suppressed by DS 103-282 (3.3-10 mg/kg, i.p.). In the baboons, a transient protection against photomyoclonic responses was observed 1 hr after intravenous administration of DS 103-282 (2-4 mg/kg). A similar profile of action was seen after oral administration of larger doses of DS 103-282 (16-32 mg/kg). Unwanted effects of DS 103-282 included transient piloerection, slight disturbance of gait and a fall in rectal temperature in mice, and muscular hypotonia and signs of sedation in baboons. These studies demonstrate an anticonvulsant action of DS 103-282, in both rodent and primate models of epilepsy, but do not support a postsynaptic blockade in excitatory neurotransmission as the mechanism of this action.

Acoustic Stimulation↗

Unexpected potentializing effect of a tacrine derivative (9-amino-7-methoxy-1,2,3,4 tetrahydroacridine) upon the non-epileptic myoclonus in baboons Papio papio.

1. The influence of 7-methoxytacrine (7-MEOTA) on the non epileptic myoclonus of the Papio papio baboon was studied in 5 animals. 2. This type of myoclonus is thought to depend on a cholinergic system dysfunction since it can be induced by atropine and blocked by physostigmine. 3. 7-MEOTA, a tacrine derivative, is believed to display a conspicuous anticholinesterase activity but, surprisingly, it here potentiated the non epileptic myoclonus occuring either spontaneously or induced by atropine. 4. In baboons not spontaneously presenting the non epileptic myoclonus, 7-MEOTA induced the myoclonus in a fashion similar to atropine; such a myoclonus was blocked by physostigmine. 5. These data indicate a possible antagonist action of tacrine on the muscarinic acetylcholine receptor. From these data, it is suggested that caution is necessary when introducing a tacrine derivative in clinical practice.

Animals↗

Electrographic studies of the effects of RP 60180, a novel kappa agonist, on the photosensitive baboon Papio papio.

1. The authors describe here the effects of intravenous administration of RP 60180, a novel kappa agonist, on conscious baboons of the species Papio papio, which spontaneously present photically induced epileptic responses. 2. Animals (n = 2) were chronically implanted with epidural recording electrodes and tested whilst seated in a primate chair. The electrocorticogram (ECoG) and electrocardiogram (ECG) were recorded during a control period of at least 30 minutes before the injection of RP 60180 (1 to 4.5 mg/kg i.v.) and immediately afterwards. 3. Qualitatively, up to the dose of 4.5 mg/kg i.v., RP 60180 did not modify ECoG background in term of paroxysmal activity in comparison with that observed during the control period. It did not cause any manifest focal or generalized seizure discharges, nor did it consistently enhance or reduce photically induced myoclonic responses. 4. From the dose of 1 mg/kg i.v., RP 60180 slowed ECG frequency. This effect, which lasted for about 30 minutes post-injection, was most often seen at the higher doses. 5. In another set of experiments, one baboon received the kappa agonist U-50488 (a benzacetamide derivative of spiradoline) at 1 and 3 mg/kg i.v. U-50488, at 3 and to a lesser degree at 1 mg/kg i.v., induced paroxysmal bursts of slow wave ECoG activity and a slowing of the ECG. These effects lasted about 1 hour post-drug administration. During this period, we observed spontaneous vocalization, as if the animal were complaining, as well as shaking.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗