R. Naquet

Audiogenic seizures evoked in DBA/2 mice inducec-fos oncogene expression into subcortical auditory nuclei

Recently the nuclear proto-oncogene c-fos has been shown to be rapidly and transiently expressed following seizures in many types of epilepsies. Until now, immunohistochemical as well as in situ hybridization studies have reported that the dentate gyrus of the hippocampus and most of the cortical areas were invariably heavily labeled. In order to see whether this distribution was reproduced or not in a model of epilepsy which has been proved to not involve these structures, a study was performed on genetically epilepsy-prone DBA/2 mice. Here we show that following audiogenic seizures, c-fos oncoprotein is not expressed in cortical and limbic structures but rather mapped the subcortical auditory nuclei.

Central type benzodiazepine binding sites: A positron emission tomography study in the baboon's brain

An in vivo characterization of specific central type benzodiazepine (BZD) binding sites, labelled with [11C]Ro 15-1788 was performed, using positron emission tomography. After i.v. injection of 10 mCi [11C]Ro 15-1788 (corresponding to 1 nmol/kg), sequential quantitative tomographic slices of the brain were obtained during 80 min. In some experiments various doses of different cold drugs (BZD agonist or antagonist) were injected i.v. subsequently in order to explore the specificity of the binding of the radioligand in brain structures. The main criteria usually utilized in vitro to demonstrate a specific binding to receptors, such as regional distribution, stereospecificity and saturability of the binding and pharmacological effect linked to the receptors occupancy, were demonstrated in the brain of a living baboon.

Behavioural and electrographic effects of L-5-hydroxytryptophan and D, L-parachlorophenyl-alanine on epileptic Senegalese baboon (Papio papio).

Abstract In the Senegalese baboon, Papio papio , the behavioural and electrographic effects of the serotonin precursor, L-5-hydroxytryptophan (5-HTP) and a serotonin depletor, D,L-para-chlorophenylalanine (pCPA) were examined with special attention to the pre-existing photosensitivity and epileptiform electrographic activity. 1. 1. L-5-HTP (10–35 mg/kg) depressed motor and EEG responses to photic stimulation for 1–4 h after injection. 2. 2. 48 h after D,L-pCPA (200–300 mg/kg), myoclonic responses to photic stimulation were enhanced. Consistent reduction of photosensitivity was observed 4–7 days after pCPA. 3. 3. Both drugs activated spontaneous epileptiform electrographic abnormalities. These changes in background activity were often chronologically independent of the changes in photically induced responses. 4. 4. It is suggested that serotonergic systems can play a role in the photomyoclonic syndrome in Papio papio .

Paroxysmal Responses to Intermittent Light Stimulation in a Population of Baboons (Papio papio)

In a population of 100 Papio papio, 9 Erythrocebus patas and 8 Cercopithecus aethiops sabaeus, 75 papios, 1 patas and 1 sabaeus exhibited paroxysmal activity to intermittent photic stimulation which resembled the photo‐myoclonic syndrome in man. Factors of age, sex, diet, climatic conditions and background lighting appeared unrelated to the response. In only 4 of the 117 subjects had there been any surgical intervention, anesthesia or other drug administration in the past history of the animal.

Epileptogenic γ-aminobutyric acid-withdrawal syndrome after chronic, intracortical infusion in baboons

We studied the effects of chronic (7 days) infusion of GABA (100 micrograms/microliter) applied intracortically into the fronto-rolandic (FR) area of baboons, via osmotic minipumps. In photosensitive animals, bilateral GABA application produced a complete blockade of the paroxysmal discharges and associated clinical signs induced by intermittent light stimulation. Unilateral administration had similar effects, although these developed more gradually. At the end of the infusion period, both photosensitive and non-photosensitive animals showed a transitory state (3-4 days) of cortical hyperexcitability (spontaneous epileptogenic activity) localized to the infused area. The data indicate a role of GABA both in the natural photosensitivity of the epileptic baboon and in the withdrawal syndrome consecutive to the sudden interruption of chronically enhanced GABA levels in the FR territories of this monkey.

Multiunitary activity naalysis of cortical and subcortical structures in paroxysmal discharges and grand mal seizures in photosensitve baboons

Abstract Cortical and subcortical multiunitary activities (MUA) and EEG were s0imultaneously recorded in baboons made photosensitive bu a subconvulsant does of dl -allglycine. Intermittent light stimulation (ILS) trains induced in these animals fronto-rolandic (FR) paroxysmal discharges (PDs, constituted as spikes and waves) and grand mal seizures. During the induction of FR PDs by ILS trains, the visual structures (occipital cortex, colliculi superiors, pulvinar) showed a significant MUA increase which was not related to teh PD spike or wave but correlated with the flashes. The first structure showing bursts of MUA that frequently preceded the PD appearance was the FR cortex. When PDs appeared, the brusts were related to the spikes of PDs and were followed by an inhibition during the slow wave. The pontine and mesencephalic formations and the facial nuclei were activated in bursts after the FR PDs had reached a certain amplitude. The thalamic nuclei ventralis lateralis, centrum medianum and lateralis posterior were activated only later, when the FR PDs had reached an even greater amplitude. It is suggested that the activation of visual structures is necessary for FR PD appearance. The secondary pontine and mesencephalic activation could reinforce that of the FR cortex and then the thalamus, and could determine the myoclonus observed in unparalysed animals. When the ILS is continued, grand mal seizures appear. The onset of the seizures could be linked to the loss of FR cortical control of the subcortical structures. The resulting reticular activation would be responsible for the vasomotor modifications which constitute the first clinical signs of a seizures.

Effects of opiate-like peptides, morphine, and naloxone in the photosensitive baboon, papio papio

The effects of intracerebroventricular (i.c.v.) or systemic injections of Met- or Leu-enkephalin, beta-endorphin, FK 33.824 (D-Ala2, MePhe4, Met(O5)-ol-enkephalin) and of morphine and naloxone have been studied in baboons, Papio papio, which spontaneously show photically induced epileptic responses. Animals were chronically implanted with epidural or deep recording electrodes and a cannula in one lateral ventricle, and tested whilst seated in a primate chair. In some animals the natural syndrome was enhanced by the prior administration of DL-allylglycine, 100--200 mg/kg, i.v. Met- or Leu-enkephalin, 1--10 mg, i.c.v., did not lead to any manifest focal or generalized seizure discharges. Nor did it lead to any consistent enhancement or reduction of photically induced myoclonic responses (as tested 5--10 min after injection). beta-Endorphin, 0.1--0.5 mg, i.c.v., did not enhance or impair photically induced myoclonic responses. FK 33.824, 0.1--0.5 mg, i.c.v., depressed respiration and slowed EEG background rhythms for 9--15 h. This was associated with a loss of myoclonic responses to photic stimulation. These effects were reversed for 20--40 min following the injection of naloxone, 1 mg/kg i.m. A depression of respiration and a slowing of EEG rhythms was seen beginning 5--20 min after FK 33.824, 2 or 4 mg/kg, i.v. The higher dose also abolished photically induced myoclonic responses. Naloxone, 1 mg/kg, definitively reversed these effects. Morphine, 5--10 mg i.c.v., tended to increase the latency to onset of generalized myoclonus during photic stimulation. Myoclonic responses were delayed or diminished after morphine, 5 mg/kg, i.m. Naloxone, 1--2 mg/kg i.m., reversed this effect. Naloxone, 0.2--5.0 mg/kg i.m., alone, did not significantly modify photically induced myoclonus, either in animals of low or high initial responsiveness, or in those pretreated with allylglycine.

Proconvulsant effects in baboons of β-carboline, a putative endogenous ligand for benzodiazepine receptors

beta-Carboline-3-carboxylic acid ethyl ester (beta-CCE) was tested on two models of epilepsy in the baboon: kainic acid-induced limbic status epilepticus and photosensitive epilepsy. Beta-CCE, at very low doses ranging from 8 to 100 microgram/kg (i.v.), induced a reactivation of the limbic focus and photomyoclonic and generalized seizures in photosensitive and non-photosensitive baboons. The proconvulsant effect of beta-CCE may be associated with its binding to a particular subclass of benzodiazepine receptors.

Cerebrospinal fluid amino acid and monoamine metabolite levels ofPapio papio: correlation witphotosensitivity

Several putative neurotransmitter amino acids and monoamine metabolites were measured in the cerebrospinal fluid of spontaneously photosensitive baboons (Papio papio) at different periods with varying degrees of photosensitivity in the same animals. At maximum photosensitivity the inhibitory amino acids gamma-aminobutyric acid and taurine were lower, and those of asparagine (metabolite of the excitatory amino acid aspartate) were higher, than when the animals were not photosensitive. Thus a decreased inhibition and perhaps increased excitation correlates with the level of photosensitivity.

The kinetics and displacement of [11C]flunitrazepam in the brain of the living baboon

The distribution and kinetics of [11C]flunitrazepam in the brain were studied by positron emission tomography in the living baboon. Flunitrazepam was labelled on the methyl group with the 20 min positron emitter carbon 11. Fifteen to 25 mCi corresponding to 15-30 nmol were injected i.v. and sequential tomographic pictures of the brain were obtained. In some experiments, therapeutic doses of various benzodiazepines were injected i.v. subsequently in order to study the displacement of the radioactive ligand from brain structures. Lorazepam was shown to displace [11C]flunitrazepam from brain tissue, although other benzodiazepines (chlordiazepoxide, Ro 116896 and Ro 116893) led to a redistribution of the radioactive ligand in the body accompanied by an increase of brain radioactivity.