Ibotenic acid-induced nigral lesion and limbic seizure in cats.

The degenerative lesions of bilateral substantia nigra (SN) were made by means of microinjections of ibotenic acid (IBO) solutions and influences upon kainic acid (KA)-induced seizures were studied. IBO solutions were injected bilaterally into SN and circumscribed degenerative lesions were made within the bilateral SN. In a control group, phosphate buffer solutions were injected in the bilateral SN. More than one week after the procedures, 1 microgram KA was injected into unilateral amygdala via implanted cannula and limbic seizures were induced. The destruction of SN accelerated the secondary generalization of the limbic seizure within 3 days after the KA injection while no secondary generalization was observed within 3 days in the control group. The fact suggests that GABAergic systems of the substantia nigra and/or ascending norepinephrine pathway have a strong inhibitory influence on the secondary generalization of limbic seizures. The hypothesis of nigral mechanisms as a control system for secondary generalization is discussed.

[Effect of trihexyphenidyl-HCL on posttraumatic prolonged disturbance of consciousness: report of two cases].

Cases involving two patients who presented post-traumatic prolonged disturbance of consciousness (PTPDC), namely akinetic mutism, and recovered from it after treatment with trihexyphenidyl were reported. Case 1: A seventy-one-year-old farmer. Five months after head injury, when he was first admitted to us, he was stable with signs of oligokinesia, katatonic posture, speechlessness, rigid muscle tones and positive cog-wheel phenomenon. One week after administration of the drug, his speech and voluntary movement improved remarkably. Two months after the treatment, he was able to walk, and was discharged from the hospital. Case 2: A forty-six-year-old man sustained major head trauma. In the acute stage, he was comatose with decerebrate posture. On the 15th hospital day, he showed a state of akinetic mutism with normal sleep - wakefulness cycle. Evacuation of the collected subdural fluid was done one month after the injury, which resulted in no change in his clinical state. Five months after the injury, trihexyphenidyl treatment was begun. A few days after the treatment, his motor activity and his facial expression obviously improved. One week after, he mimicked the word 'o-ha-yo (good morning)' after the physician's greeting. CT scan and magnetic resonance imaging in the chronic state of these patients showed bifrontal cerebral white matter lesions, which indicated old cerebral contusion. No brain stem lesions were detected with these examinations. Our two cases clearly did not belong to the category of post-traumatic parkinsonism because of their clinical courses, and their features shown in radiological examinations. However the anti-parkinsonian drug, trihexyphenidyl was effective.(ABSTRACT TRUNCATED AT 250 WORDS)

[Acute effect of penicillin G on feline models of focal epilepsy].

Penicillin is well known as a potent convulsive agent. A cortical topical, intracerebral or systemic administration of penicillin produces abnormal and paroxysmal activity which may lead to seizure, and has been used in the investigation of the mechanisms of epilepsy. This is a report on the studies of an acute effect of potassium penicillin G on two models of experimental focal epilepsy: a) amygdaloid kindling model, and b) kainic acid-induced limbic seizure model. Twelve adult cats for amygdaloid kindling model (kindling group), six for KA-induced limbic seizure model (KA group) and four for a control group were prepared for this study. In kindling group, after completion of kindling procedure, 40-60 X 10(4) unit/kg of potassium penicillin G (PC), dissolved in sterilized normal saline, was injected intraperitoneally during an interictal period. In KA group, 1 micrograms of KA was injected into the left amygdala. Limbic seizures occurred frequently during the initial 5 hours but subsided completely within 3 days. After a latent period, spontaneous secondarily generalized convulsion occurred from 30 to 60 days after KA injection. The cats were completely normal in their behavior during the interictal period. During the interictal stage after the first generalized convulsion has been observed, 15-20 X 10(4) unit/kg of PC was injected intraperitoneally. In the control group, 40-60 X 10(4) unit/kg was injected intraperitoneally. Electroclinical observations were continued until 5 hours after PC injection in three groups. In the control group, no cats developed generalized convulsion. In the kindling group, 4 of 12 cats developed focal amygdaloid seizures with secondary generalization by nearly the identical doses required in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

[Acute effect of flunarizine on amygdaloid kindling in cats].

Flunarizine (Flu), a difluoro derivative of cinnarizine, is well known as a calcium channel blocker. Recently, many authors have reported an antiepileptic effect of this drug in experimental models of epilepsy and in the clinical use. In the present study, acute effect of Flu was examined in the amygdaloid kindled cats, and add-on effects of Flu with valproic acid (VA) was also studied. Twenty three cats were used in this study. Amygdaloid kindling was established as previously reported. A strength of stimulations for kindling was at 300 microA. Same strength was used after completion of kindling. In this "high intensity" kindling, daily stimulation invariably induced initial amygdalo-hippocampal seizures followed by secondarily generalized seizures after completion of kindling. In addition, one amygdaloid stimulation was given daily for 5 days after completion of kindling in order to make it certain to induce secondarily generalized seizures. Drugs were injected on the 6th day intraperitoneally one or two hours before the stimulation daily given for 5 days after completion of kindling (GS 6) or after 4 days clearance period of previous administration of the drug. Pretreatment with Flu (high doses: 30 or 50 mg/kg, i.p.) abolished the secondary generalization after the GS 6. With this high doses of Flu animals died of side effect within 3 days after intraperitoneal administration. With lower doses of Flu less than 3 mg/kg, i.p. of Flu no side effect was encountered but antiepileptic effect was not obtained as well. Then add-on trials of Flu were performed with valproic acid (VA). The most effective combination was 100 mg/kg, i.p. of VA with 3 mg/kg, i.p. of Flu. With this combination, secondary generalization was suppressed at a ratio of 54.5% The results confirmed antiepileptic effect of Flu and add-on effect of Flu to VA.(ABSTRACT TRUNCATED AT 250 WORDS)

[Epileptogenic properties of quisqualic acid: microinjection into the unilateral amygdala in cats].

The present studies demonstrated that the microinjection of quisqualic acid (QA) into unilateral amygdala in chronically implanted cats resulted in various types of limbic seizures in accordance with injected doses. The epileptogenic potency of QA in the induction of epileptic seizures was lower then that of kainic acid (KA), which has also been demonstrated in our previous studies. Electroencephalographic changes and clinical manifestations of QA-induced epilepsy were less prominent as compared with those of KA-induced epilepsy. Five micrograms of QA resulted in pure amygdaloid seizures. The moderate dose administration of QA (15 micrograms) was suitable to observe limbic status. Both doses of QA elicited similar characteristic epileptic patterns on EEG, which was quite distinguishable from those of KA. In pathological study, mild degeneration of hippocampal pyramidal cell layer was observed in the cases injected 15 micrograms of QA. These electro-clinical and pathological features are interesting in similarities to those of human complex partial seizures, mesial temporal sclerosis. In conclusion, the strict dose dependency of QA in the production of limbic seizures is a valid advantage for an experimental model of a complex partial epilepsy in man.

The influence of light stimulation on subcortical potentials evoked by single flashes in photosensitive Papio papio.

Visual evoked potentials (VEPs) from the frontorolandic (FR) cortex and from subcortical nuclei (colliculi superioris, pulvinar, corpori geniculati lateralis, centrum medianum, ventralis lateralis) and from pontine reticular formation were analyzed in Papio papio monkeys rendered photosensitive by a subconvulsant dose of allylglycine. The VEPs induced by single flashes were compared statistically with those induced by flashes preceded by trains of intermittent light stimulation (ILS). This latter mode of stimulation provoked the appearance of paroxysmal VEPs (PVEPs) in the FR cortex with the same morphology as the spikes and waves induced in this area by the ILS. The aim of our research was to provide evidence for the possible implication of the subcortical structures which we have studied in the elaboration of PVEPs and thus of spikes and waves. The VEPs recorded at the thalamic and pontine levels were modified when PVEPs were present. These modifications varied according to the site, but subcortical VEPs were never paroxysmal. In structures with visual functions (colliculi superioris, corpori geniculati lateralis), the VEPs were modified by the ILS, but showed more marked changes when PVEPs were present. Thus, these structures may contribute to the genesis of PVEPs. In the other structures (centrum medianum, ventralis lateralis, and pontine reticular formation), modifications of the VEPs occurred only when PVEPs were present. Thus, these structures would be only secondarily involved. We also present preliminary results concerning the effects of lesioning the pulvinar and the ventralis lateralis on the susceptibility of the FR cortex to produce spikes and waves during ILS.(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous secondarily generalized seizures induced by a single microinjection of kainic acid into unilateral amygdala in cats.

Electrographic and clinical observations were made for 6 months after the injection of kainic acid (KA) solution (1 microgram in 1 microliter of phosphate buffer solution) through a chronically implanted cannula into a unilateral amygdala of freely moving and non-anesthetized cats. The control group (phosphate buffer group) showed no change during the observation period. After the injection of kainic acid, focal status epilepticus in the limbic system was observed for 3 days. Cats recovered clinically but persistent IIDs were observed at the injected site of the amygdala. These IIDs increased in amplitude and frequency and began to trigger spontaneous amygdaloid seizures. Secondary epileptogenic foci were then established in the contralateral amygdala, and amygdaloid seizures began to occur alternatively on both sides and finally trigger frequent limbic seizures from 20 to 40 days after KA injection. Spontaneous secondarily generalized seizures developed about 30 days after KA injection and occurred once or twice a week thereafter. The animals were completely normal in their behavior during the interictal phase. This is an excellent model of experimental epilepsy for the investigation of the mechanism of limbic seizure development and further study using this model will provide informations useful for the therapy of temporal lobe epilepsy in man.

Quisqualic acid-induced hippocampal seizures in unanesthetized cats.

An intrahippocampal injection of quisqualic acid (QA) was made in chronically implanted freely moving unanesthetized cats and electrographic and clinical observations were made. Fourteen to 40 micrograms of QA injection resulted in a mild limbic seizure within 24 h after QA injection. Some cats demonstrated a pure hippocampal seizure on an electroencephalogram. Electrographic changes and clinical manifestations were less prominent as compared with those of kainic acid. Histopathological examination showed a selective loss of pyramidal cell layer of the CA3 portion in the injected side of the dorsal hippocampus. A mild but constant epileptogenic potency of QA has an advantage for an experimental model of temporal lobe epilepsy in man.

Visualization by positron emission tomography of the apparent regional heterogeneity of central type benzodiazepine receptors in the brain of living baboons.

The feasibility of visualizing the heterogeneity of benzodiazepine (BDZ) receptors in the brain of living baboons was investigated using Positron Emission Tomography. Ethyl 8-fluoro-5,6-dihydro-5-methyl 6-oxo-4H-imidazo (1,5-a) (1, 4) benzodiazepine-3-carboxylate (RO 15 1788) labelled by carbon 11 (11C-RO 15 1788) was I.V. injected for the "in vivo" labelling of the central type BDZ receptors. Displacement experiments were performed 20 minutes after the administration of the radioligand by two different cold drugs: RO 15 1788 which has an equal affinity for central type BDZ receptors, and propyl B-Carboline-3-carboxylate (B-CCP) which favours the sites located in the cerebellum. Different sensitivities to these two drugs displacement of 11C-RO 15 1788 binding "in vivo" were observed: on the one hand in the regional localization of the displacement, and on the other hand, in the amount of the radioactivity displaced. The apparent interregional heterogeneity of the displacement seen in the cerebellum and in the temporal cortex are discussed in terms of discrepancies observed "in vitro" at physiological temperature, between cerebellar and non-cerebellar BDZ central type binding sites.

Electroencephalographic, behavioral, and histopathologic features of seizures induced by intra-amygdala application of folic acid in cats.

The effects of intracerebral injection of folic acid are still controversial. We studied the electroencephalographic, behavioral, and histopathologic consequences of the seizures induced by intra-amygdala administration of various doses of FA in freely moving cats. The severity of the seizures was dose-dependant. For doses of 25 and 50 nmol, single low-amplitude spikes appeared in the amygdala 15 to 20 min after injection and a typical amygdala symptomatology was observed. From doses of 100 nmol recurrent limbic seizures occurred 40 to 80 min after injection. Finally, from doses of 150 nmol secondarily generalized seizures were induced, which could be followed by death 4 to 6 h after injection. The severity of the cerebral lesions was related to both the dose and the paroxysmal manifestations. In cases with short survival time (6 h) and few seizures the pathology was restricted to a lymphocytic and glial reaction with some ischemic cells at the injected site. In cases with status epilepticus, edema and neuronal degeneration was observed in the hippocampus, amygdala, thalamic nuclei of the midline, entorhinal cortex, and cerebellum. No neuronal alteration at the injected site was observed. For longer survival times (8 days) edema was less severe, but hyperchromatic cells were still numerous. These results, compared with those of intra-amygdala administration of kainic acid, suggest that pathologic lesions induced in cats by folic acid more closely resemble those described in man after some status epilepticus.

Hypnotic action of ethyl beta-carboline-3-carboxylate, a benzodiazepine receptor antagonist, in cats.

The present study demonstrates that ethyl beta-carboline-3-carboxylate (beta-CCE), a benzodiazepine receptor antagonist, has hypnotic and sedative actions in cats. Moreover, at a dose that does not by itself affect sleep, beta-CCE reverses the action of diazepam on sleep organization. The hypnotic effect of subcutaneous administration of beta-CCE (5 mg/kg) lasts for 3-4 h. During this period, deep slow wave sleep (deep non-REM sleep) and paradoxical sleep (REM sleep) significantly increase, while wakefulness markedly decreases. These results, which are quite opposite to the effects of benzodiazepines on sleep organization in cats, support the notion that beta-CCE also acts as a benzodiazepine antagonist of sleep organization.

[Potent convulsant effects of a benzodiazepine inverse agonist, methyl beta-carboline-3-carboxylate in cats].

The convulsant properties of methyl beta-carboline-3-carboxylate (beta-CCM), which is a homologue of a putative benzodiazepine receptor ligand in the mammalian central nervous system, were examined in cats. Subcutaneous injection of 0.5 mg/kg of the beta-CCM produced various degrees of myoclonic jerks always accompanied by cortical spike burst. Some autonomic symptoms such as tachypnea, hypersecretion of thick mucous saliva, vomiting and mydriasis were also presented. Subcutaneous injection of 1.0 mg/kg of the compound induced a generalized tonic-clonic convulsion. Injection of the same amount of the drug 1 hour later in the same cats failed to provoke a generalized seizure. Repeated injection of the same dose 3 hours later provoked a generalized seizure, but with a longer latency. However, repetition of the experiments 24 hours after or 10 days after the first injection consistently induced the same type of generalized seizure with the same latency as the first injections. These results support the suggestion that the pharmacological effect, especially the convulsive effect, of beta-CCM is dose-related, reversible and reproducible in the same cats and among different cats. Moreover, the postictal refractory period in this model of epilepsy may continue about for 3 hours.

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 receptor's occupancy, were demonstrated in the brain of a living baboon.

The partial benzodiazepine agonist properties of Ro 15-1788 in pentylenetetrazol-induced seizures in cats.

The effects of Ro 15-1788, a specific benzodiazepine antagonist, were studied on pentylenetetrazol-induced seizures in cats. Ro 15-1788 decreased the number of myoclonic jerks induced by a subconvulsive dose of pentylenetetrazol (12.5 mg/kg, i.m.). Ro 15-1788 suppressed generalized convulsive seizures induced by a minimal convulsive dose of pentylenetetrazol (25-35 mg/kg), but did not block the effects of higher doses (35-45 mg/kg). These results indicate that Ro 15-1788 is not a pure benzodiazepine antagonist, but has partial agonistic properties.

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.

[Rapid hippocampal kindling following intraamygdaloid injection of quisqualic acid in cats].

Quisqualic acid (QA) is a potent neuroexcitant and a heterocyclic analogue of glutamate as is kainic acid. Twenty micrograms of QA in unilateral lateral amygdaloid nucleus of cats produced a transient limbic status epilepticus lasting 20-30 hours. Over 14 days after recovery from the limbic status, the animals received daily electrical stimulation to the ipsilateral hippocampus at the intensity of afterdischarge threshold which was determined before the injection of QA. These stimulations resulted in secondarily generalized convulsive seizures in all animals within 4 to 12 days. Spontaneous secondarily generalized seizures were confirmed in two cats after completion of the hippocampal kindling. This rapid completion of the kindling process is interesting phenomenon in contrast to the report that the hippocampal kindling took nearly 60 days. This rapid completion of the kindling effect is considered to be due to the transfer effect (Goddard, 1975) established in the ipsilateral hippocampus by severe bombardments from the amygdala stimulated by the injection of QA as the primary focus. In addition, the pathological changes in the amygdala and hippocampus on the injected side might be related to the rapid kindling process of the ipsilateral hippocampus as the irritable foci.

Abortive amygdaloid kindled seizures following microinjection of gamma-vinyl-GABA in the vicinity of substantia nigra in rats.

The effects of microinjection of a GABA-elevating substance (gamma-vinyl-GABA) in the substantia nigra were assessed on kindled convulsive seizures induced by daily appropriate amygdaloid stimulation in the rat. Bilateral administration of 20 micrograms of gamma-vinyl-GABA strongly reduced the afterdischarge duration of the seizures without significantly modifying the motor convulsions. This effect was noted 24 h after injection and lasted for up to 48 h. Administration of gamma-vinyl-GABA in structures 1.5 mm distant from the substantia nigra had no effect on kindled seizures. It is suggested that the substantia nigra may intervene in a negative feedback system that tends to suppress the paroxysmal activity initiated from the amygdala.

[In vivo study of benzodiazepine receptors using positron emission tomography]. / Etude "in vivo" des récepteurs aux benzodiazépines par tomographie par émission de positons.

The results obtained by positron-emission tomography in an "in vivo" study on the baboon using a benzodiazepine (flunitrazepam) labeled with carbon-11 are presented. The specificity of "in vivo" binding of Flunitrazepam-11C was demonstrated by competition with Lorazepam in the brain, but it was not possible to verify the criterium of stereospecificity "in vivo". The preliminary results of a study carried out under the same conditions on RO 15 1788 11C show the interest of using this labeled antagonist as an "in vivo" ligand for the specific binding sites of benzodiazepines in positron-emission tomography.