Anne Valin

Methyl-β-carboline-induced convulsions are antagonized by Ro 15-1788 and by propyl-β-carboline

Abstract Injected i.v. into baboons, Ro 15-1788 (a benzodiazepine antagonist) and propyl-β-carboline-3-carboxylate did not modify either the behavior or the electroencephalogram at doses up to 2 mg/kg. Methyl-β-carboline-3-carboxylate is a potent convulsant at doses of 20 μg/kg in photosensitive baboons and 100 μg/kg in non-photosensitive baboons. These convulsive doses of methyl-β-carboline-3-carboxylate are effectively antagonized by 0.5 mg/kg of Ro 15-1788 and also by 2 mg/kg of propyl-β-carboline-3-carboxylate.

Physostigmine antagonizes benzodiazepine-induced myoclonus in the baboon, Papio papio.

The antagonism of some benzodiazepine (Bz) actions by physostigmine was investigated in 4 Papio papio baboons. As a model of these actions, the myoclonus induced in this species by clonazepam i.m. administration was used. The baboon develops, 20-30 min after Bz i.m. injection, a non-epileptic myoclonus characterized by clinical symptomatology (jerks involving mainly the neck and the trunk bilaterally), by the absence of any correlative EEG discharge, and by its facilitation during movement. This Bz-induced myoclonus resembles the intention myoclonus of human patients, as seen for example after anoxia. In the present series, the effect of physostigmine i.v. injection on the frequency of clonazepam-induced myoclonus was tested. Physostigmine produces a rapid and total abolition of the myoclonus, and this effect lasts for a period which corresponds to the pharmacological activity of physostigmine. On the contrary, atropine i.v. injection considerably increases the amount of Bz-induced myoclonus. These results allow the existence of an anticholinergic action of benzodiazepines, reversed by physostigmine, and the theory that the myoclonus would be the consequence of a cholinergic system depression to be hypothesized.

Role of the forebrain commissure and hemispheric independence in photosensitive response of epileptic baboon, Papio papio

The effect of monocular intermittent light stimulation (ILS) of either hemivisual field (HVF) of the full visual field (FVF) was examined in Papio papio with or without forebrain bisection. ILS of the HVF or the FVF in non-bisected baboons produced bisymmetrical and bisynchronous spike and wave which was followed by a self-sustained seizure without EEG evidence of hemispheric independence. ILS of the FVF in bisected baboons also produced bilateral spike and wave and self-sustained seizures of a similar nature. With ILS of the HVF in bisected baboons, EEG seizures lateralized largely to the contralateral hemisphere and when the ILS of the HVF was switched to the other eye similarly lateralized spike and wave and a self-sustained seizure were produced in the other hemisphere. These findings suggest that (a) the forebrain commissure, most probably the corpus callosum (and possibly the hippocampal commissure), plays a major but not unique role in the bisynchronization and generalization of the ILS-induced spike and wave and the self-sustained seizures, and (b) each hemisphere possesses independent cerebral excitability to the ILS.

Opposite effects of lorazepam on two kinds of myoclonus in the photosensitive Papio papio

The action of lorazepam was studied in photosensitive baboons. Animals were either naturally very photosensitive or rendered photosensitive by a previous injection of allylglycine. Intravenous administration of varying doses, from 0.05 to 0.5 mg/kg, of lorazepam blocked the myoclonus induced by intermittent light stimulation in all the animals. However, in the naturally photosensitive baboon the injection of lorazepam favoured the appearance of spontaneous myoclonus with no important EEG modification. This myoclonus is different from that induced by intermittent light stimulation, which is always preceded by spike-wave cortical discharges. Lorazepam-induced myoclonus appears during the period when the animal is not photosensitive and its origin is probably in the medulla or in the brain stem.

Les crises induites — Ou non — Par la stimulation lumineuse intermittente chez le « Papio papioaprès injection d'allylglycine

Summary Allylglycine, an inhibitor of GABA synthesis, produces increased sensitivity to photic stimulation and in convulsant doses spontaneous seizures arising occipitally in the baboon ( Horton and Meldrum, 1973 ). In this study, convulsant doses of allylglycine induced either sharp wave and polyspike fronto-rolandic discharges (FR) or critical posterior discharges which then reinforce the fronto-rolandic spikes. A seizure may then arise from the fronto-rolandic region and secondarily spread to the rest of the cerebral cortex. Intermittent photic stimulation produces a reinforcement of the fronto-rolandic sharp waves and can also induce self-maintaining mechanisms similar to those just described. In this situation, however, and with the animals paralysed with Flaxedil no seizures arising occipitally have been observed. The role of the occipital cortex as the sensory visual and somatic afferent in photosensitive epilepsy in the baboon is discussed in the light of these results.

Differential effects of the benzodiazepine antagonist Ro 15-1788 on two types of myoclonus in baboon Papio papio ☆

Certain benzodiazepines (BZs) like lorazepam, diazepam or clonazepam induce myoclonus jerks in photosensitive and non-photosensitive baboons. Papio papio, which are not accompanied by EEG paroxysmal discharges (type B). The effect of the selective BZ antagonist R0 15-1788 was evaluated in this myoclonus. Ro 15-1788 completely blocked type B myoclonus without decreasing the level of vigilance in the two types of baboons, and reversed the antiepileptic action of the BZs in the photosensitive ones, permitting the reappearance of myoclonus following EEG paroxysmal discharges (type A). L-5-hydroxytryptophan and progabide also blocked type B myoclonus, but the blockade was only transiently effective and was always accompanied by slight drowsiness.

Myoclonies induites par certaines benzodiazepines chez le Papio papio. Comparaison avec les myoclonies induites par la stimulation lumineuse intermittente

Papio papio may show two different kinds of myoclonus. A first type corresponds to myoclonus induced by photic stimulation (25 Hz). This type is always preceded by paroxysmal discharges. Another type of myoclonus may be induced, or at least facilitated, by some benzodiazepines, especially lorazepam and, to a lesser extent, diazepam. This type is neither preceded nor accompanied by paroxysmal discharges. A single injection of lorazepam (1 mg/kg i.v.) blocks the first type of myoclonus but favors the appearance of the second. However, these effects do not follow the same evolution; while myoclonus induced by photic stimulation disappears immediately after the injection, benzodiazepine-induced myoclonus appears only 10-15 min. Furthermore, whereas the former reappears after 150-210 min, the latter may persist for a longer time (up to 1 h). A preliminary pharmacologic study of benzodiazepine-induced myoclonus indicates that drugs increasing brain GABA level block this type of myoclonus. The possible reticular origin of benzodiazepine-induced myoclonus is suggested.

Paroxysmal visual evoked potentials (PVEPs) in Papio papio. II. Evidence for a facilitatory effect of intermittent photic stimulation

Abstract The existence of fronto-rolandic (FR) visual evoked potentials of very large amplitude (>1000 μV) in the photosensitive Papio papio , or in those made photosensitive by an injection of allylglycine, is related to the presentation of intermittent light stimulation (ILS). The temporal evolution of these paroxysmal visual evoked potentials (PVEPs) after standardized series of stimuli has been evaluated in two contexts. First, it has been compared with the evolution of the paroxysmal discharges (PDs) occurring during ILS. Secondly, it has been studied either in awake animals placed in a restraining chair or paralysed by a curare agent and ventilated artificially. In non-paralysed baboons, either photosensitive or having received an injection of allylglycine, ILS induces FR PDs grouped in bursts and possibly followed by generalized seizures. In this situation the PVEPs are difficult to obtain and occur consecutive to the appearance of the PDs. In the paralysed photosensitive baboon PDs only occur after the repetition of a considerable number of stimuli and no seizure can be induced. The frequency of occurrence of the PVEPs is low for the first stimulation but increases subsequently to reach high values. In the paralysed baboons after an injection of allylglycine, the PVEPs most often precede the PDs, have a high frequency of occurrence and have an average amplitude larger than that observed in non-paralysed animals. In all these experimental situations the temporal evolution of the PEVPs presents two aspects: facilitation of brief duration marked by higher voltage PVEPs for the stimuli which immediately follow the ILS, and a longer term facilitation marked by an increase in the average amplitude of the PVEPs as the series of ILS are repeated. FR evoked potentials of large amplitude were also obtained for subcutaneous electrical stimulation of the hand, in the paralysed baboon after allylglycine. Following these observations, the question arises of the origin of the facilitation of PVEPs. Our results furnish no argument in favour of a facilitation having its origin in the non-specific structures such as the reticular formation. Finally, our observations confirm the different reactivity of the PDs and the PVEPs to certain experimental conditions. This, in turn, raises the problem of the exact similarity of these two types of paroxysmal activity.

Effect of Macular and Peripheral Retina Coagulation on Photosensitive Epilepsy in the Forebrain Bisected Baboon, Papio Papio

Summary: The effects of macular and peripheral retina coagulation were examined in photosensitive baboons, Papio papio (PP), with or without forebrain bisection. The temporal part of the macula and surrounding retina of the left eye were coagulated with an Argon laser and later confirmed histologically. In forebrain nonbisected baboons, intermittent light stimulation of the operated eye produced bisymmetrical and bisynchronous spikes and waves and self‐sustained seizures. In forebrain‐bisected baboons intermittent light stimulation of the operated eye produced spikes and waves and self‐sustained seizures localized to the contralateral hemisphere. Subsequent stimulation of the nonoperated eye in the same animal produced spikes and waves and seizures either bilaterally or only in the opposite hemisphere when stimulation took place during the postictal silent period in the first hemisphere. In both cases, the tonic phase of the seizure was always bilateral but asymmetrical as shown by electromyographic recordings. Based on these data, it has been hypothesized that the tonic phase is mediated, in part, through crossed interreticular pathways, by one or both cerebral hemispheres. However, data are also compatible with a possible origin of the tonic phase of the seizure being partly localized in the medial frontal cortex. Results demonstrated (1) the usefulness of laser coagulation of the temporal portion of the macula and retina for the study of the functional independence between two cerebral hemispheres, (2) the critical role of the corpus callo‐sum (CC) in ^synchronization and generalization of the intermittent light stimulation (ILS)‐induced seizure, (3) independent excitability of each cerebral hemisphere by the ILS, and (4) the critical role of cortical visual affer‐ents for inducing epileptic phenomena in this species.

Convulsant effect of Ro 5-4864, a peripheral type benzodiazepine, on the baboon (Papio papio).

The effects of Ro 5-4864, a 1,4-benzodiazepine with a high affinity for the peripheral-type benzodiazepine (Bz) binding site, were investigated in the baboon (Papio papio), which is genetically predisposed to epilepsy. A proconvulsant effect of low doses (1-3 mg/kg, i.v.) of Ro 5-4864 was observed by studying its effect on the photic responses induced by intermittent light stimulation in non-photosensitive baboons. Higher doses of Ro 5-4864 (10 mg/kg, i.v.) were overtly convulsant. The Bzs clonazepam and diazepam blocked these convulsant actions of Ro 5-4864 whereas neither Ro 15-1788, an antagonist of central Bz binding sites, nor PK 11 195, an antagonist of peripheral Bz binding sites, had any effect. It thus appeared that the convulsant effect of Ro 5-4864 was not mediated by Bz binding sites of either the central or the peripheral type. It is possible that Ro 5-4864 exerts its convulsant action at the picrotoxin site of the central Bz receptor - gamma-aminobutyric acid receptor-chloride ionophore complex.