Robert M. Julien

Effect of Carbamazepine on the In Vitro Uptake and Release of Norepinephrine in Adrenergic Nerves of Rabbit Aorta and in Whole Brain Synaptosomes

The effects of carbamazepine, in vitro, on adrenergic neuronal and whole brain synaptosomal uptake and release of tritiated norepinephrine (3H‐NE) were assessed. At 104 M, carbamazepine inhibited :,H‐NE uptake by 22% in rabbit thoracic aorta and in brain synaptosomes. At the same concentration, carbamazepine inhibited stimulation‐induced release of 3H‐NE by 42.69c and inhibited isometric contraction in rabbit ear artery helical strips by 31.6%. At 10‐5M, carbamazepine exhibited a 17.6% inhibition of 3H‐NE uptake in brain synaptosomes in the absence of effects on transmitter release. Cocaine, 10‐4 M, and imipramine, 10‐4 M, inhibited uptake by 88% and 85%, respectively, in aorta, and cocaine, 10‐4 M, inhibited synaptosomal uptake by 67.7%. Since antiepileptic blood levels of carbamazepine range between 1.3 and 3.0 × 10‐5 M, it was concluded that the observed effects of carbamazepine are insufficient to account for the anticonvulsant action of the drug. However, the blockade of 3H‐NE uptake by brain synaptosomes at 10‐5 M serves to explain the recently described analeptic activity of this agent.

Biphasic effects of imipramine in experimental models of epilepsy.

In a vanety of laboratory models of experimental epilepsy, imipramine exerts a biphasic action on the CNS as manifested by antiepileptic properties at low doses and convulsant effects at higher doses. In mice, imipramine (17.5–25 mg/kg, i.p.) blocks maximal electroshock seizures while exerting little or no effect on pentylenetetrazol‐induced seizures. In cats, imipramine (2.5–15 mg/kg, i.v.) reduces penicillin and estrogen‐induced epileptiform discharge, shortens afterdischarge duration, and elevates afterdischarge threshold. Higher doses in mice induce neurotoxicity, including clonic seizures. In cats, doses above 20 mg/kg intensify chemically and electrically induced seizures and induce spontaneous epileptiform episodes. Such a biphasic action of imipramine may limit the drugs clinical utility as an antiepileptic agent and may provide an interesting tool for studies of catecholamines and brain excitability.

Cerebellar responses to penicillin-induced cerebral cortical epileptiform discharge

Abstract In locally anesthetized, paralyzed cats with penicillin-induced foci in sensorimotor cortex, simultaneous microelectrode recordings were made in the cerebellum and in the anterior sigmoid gyrus near the site of penicillin injection. Cerebellar recordings were made from Purkiinje cells (P-cells) and from cells located in the dentate nucleus. Data reveal distinct patterns of cerebellar responsiveness to the developing epileptogenic focus. Within 15 min after penicillin injection, high frequency (100–140 c/sec) P-cell discharges were evoked throughout the cerebellar cortex by focal “spike” activity of the cerebral cortex. These P-cells discharges outlasted short (2–10 sec) epileptiform burst; however, if P-cell discharges ceased during periods of sustained focal discharge, prolonged (up to 60 sec) convulsive episodes developed and became synchronous and maximal in both cerebral hemispheres. P-cell discharge did not reappear until after termination of the seizure. In the dentate nucleus, epileptiform activity evoked complex patterns of cellular activity. In contrast to the P-cells, cells in the dentate nucleus discharged at high frequencies during prolonged epileptiform episodes. The proposed role of the cerebellum in the control of cortical excitability is discussed.

Lidocaine in experimental epilepsy: correlation of anticonvulsant effect with blood concentrations

Abstract The convulsant and anticonvulsant actions of lidocaine HCI have been studied in cats with penicillin-induced epileptogenic foci. Following i.m. or i.v. administration, blood levels of 0.5–4.0 μg/ml were rapidly attained with concomitant reduction in epileptiform activity. Blood levels above 5.0 μg/ml were accompanied by cortical irritability and convulsions. These high blood levels, however, were not observed after intramuscular injection and anti-epileptic control was more predictable with i.m. injection than with i.v. infusion. In addition, the additive effects of diphenylhydantoin and lidocaine in reducing epileptiform activity are presented and possible mechanisms of anti-epileptic action discussed. Implications for neurophysiologic experiments requiring local anesthesia in awake, paralyzed animals and the possible use of lidocaine in acute convulsive disorders in man are likewise discussed.

Experimental Epilepsy: Cerebro-Cerebellar Interactions and Antiepileptic Drugs

Epilepsy is a term used to describe the repeated occurrence of any of the various clinical forms of convulsive seizures. Convulsive seizures appear to be the normal mode of expression of cerebral cortex and subcortical structures to an excessive, overwhelming discharge originating in a variety of loci. The tonic extensor rigidity and clonic convulsive movements of the clinical grand mal attack result from involvement of motor cortex and the spread of excitation away from the abnormal focal discharge (Adrian, 1936). One fundamental problem in epilepsy involves identification of the mechanism underlying and controlling the “highly explosive” discharges described by Kughlings Jackson (1931) which characterize the cortical epileptic focus (Ward, 1969).

Local Anesthesia and Experimental Epilepsy

Alterations of transcallosal afterdischarges were used to demonstrate that the common technique of injecting water‐soluble local anesthetic drugs into wound margins produces marked decreases of excitability in forebrain. Similar results were obtained in 20 cats with the brainstem transected at a rostral pontine level and in six paralyzed animals with intact brain.

Re-evaluation of estrogen-induced cortical and thalamic paroxysmal EEG activity in the cat

Abstract Conjugated estrogens (Premarin), piperazine-esterone-sulfate (Ogen) and esterone-3-sulfate were applied bilaterally or unilaterally to sensory-motor cortex in locally anesthetized, paralyzed cats. All these agents (1–2% concentration) initiated paroxysmal activity characterized by 2–3 c/sec spike and wave discharge that was generalized bilaterally over cortex and in the nuclei ventralis anterior, medialis dorsalis and centrum medianum of thalamus. In contrast, unilateral micro-injection (2%, 0.01 cc) of conjugated estrogens into thalamic nuclei resulted in 7–20 c/sec poly-spike activity recorded bilaterally over cortex and in the contralateral thalamus. Spike and wave discharges were not observed following thalamic injection of estrogens. Ipsilateral electrolytic lesions of either ventralis anterior or centrum medianum failed to decrease spike and wave discharge originating from a cortical focus. In chronically-isolated slabs of suprasylvian cortex, topically applied conjugated estrogens induced 1–3 c/sec spike and wave activity restricted to the isolated tissue in the absence of spread of activity to surrounding intact cortex. In contrast to the estrogenic steroids, progesterone, testosterone and diethylstillbesterol failed to initiate paroxysmal activity after bilateral topical application in concentrations of 10% although the application of either testosterone or progesterone was associated with spindle formation in some animals. These findings demonstrate a capacity of cerebral cortex to generate spike and wave discharge in the absence of subcortical influences, a generalization of spike and wave discharge from a unilateral cortical focus and an epileptogenic specificity of estrogens. The experimental spike and wave complex produced by topically-applied estrogens is discussed in reference to the epileptiform EEG of clinical petit mal or petit mal variant.

Effects of ionophores A23187 and X537A on brain calcium, catecholamines and excitability

Abstract The ionophores A23187 and X537A inhibit 45 Ca uptake by rabbit brain mitochondria and synaptosomes and also stimulate the release of accumulated 45 Ca from these preparations, but have no effect on 45 Ca binding by synaptic membranes or on total brain Ca in mice. Both agents inhibit uptake and stimulate release of 3 H-norepinephrine by rabbit P 2 synaptosomal preparations, while the NE and serotonin levels of mouse brain are depressed by X537A. The changes in Ca activities may be related both to the elevated thresholds for cortical after-discharge produced in cats by these ionophores, and to the ionophore induced reduction of pentylenetetrazol seizures in mice.

A comparative study of the efficacy of newer antiepileptic drugs on experimentally-induced febrile convulsions

In mice subjected to microwave diathermy, four new antiepileptic drugs were compared to phenobarbital for efficacy against experimentally induced febrile convulsions. Carbamazepine (10–50 mg/kg) and clonazepam (0.05–0.10 mg/kg) were ineffective against febrile seizures. Dipropylacetic acid (100–400 mg/kg) exerted effects similar to those of phenobarbital. N,N1-dimethoxymethyl-pheno-barbital (DMMP) elevated the febrile convulsive temperature threshold, depressed the rate of rise of body temperature, and decreased the intensity of the convulsion. At a dosage of 50 mg/kg, DMMP was more protective than phenobarbital (P < 0.001) in raising the convulsive threshold and in retarding the rate of rise of body temperature (P < 0.01). These antiepileptic effects of DMMP occurred at relatively non-toxic doses ( 10–200 mg/kg).

EFFECTS OF VOLATILE ANAESTHETIC AGENTS ON EEG ACTIVITY RECORDED IN LIMBIC AND SENSORY SYSTEMS

SummaryAs part of a systematic study of the effects of anaesthetic agents on cortical and subcortical activity of experimental animals, diethyl ether, halothane, methoxy-flurane, and enflurane (Ethrane) were administered to cats with chronically-implanted electrodes sterotaxically placed in selected nuclei of the sensory system (centrum medianum, ventralis posterior lateralus, and mesencephalic reticular formation) and in representative areas of the limbic system (pes hipoccampi and nucleus amygdalae). Skull electrodes were placed over frontal, parietal and/or temporal cortex.Following induction, an anaesthetic state was maintained for at least 30 minutes and deeper levels of anaesthesia were avoided. Minimal electrographic changes were observed with ether. Spiking, particularly on the limbic system, was observed with the 3 halogenated compounds. These changes were most pronounced with enflurane.RésuméAu cours d’une étude systématique sur les effets d’agents anesthésiques sur l’activité corticale et sous-corticale d’animaux de laboratoire, on a administré de l’éther de l’halothane, du méthoxyflurane et de l’Ethrane à des chats porteurs d’électrodes installées à demeure et implantées de façon stéréotaxique dans les noyaux choisis du système sensoriel et dans des zones représentant le système limbique. Des électrodes craniennes étaient placées sur le cortex frontal, pariétal et/ou temporal.Après l’induction, on maintenait l’anesthésie durant au moins 30 minutes en évitant une anesthésie profonde. L’éther produisait des changements électrographiques minimes. Les trois composés halogènes ont déclenché l’apparition d’ondes, surtout sur le système limbique, Ces changements ont été surtout prononcés avec l’Ethrane.Ainsi, nous avons l’impression que l’activité épileptoïde électrographique est comme une contre-partie de l’administration de l’Ethrane et qu’il faut en tenucompte dans l’évaluation future de l’utilité de ce produit comme anesthésique clinique. D’autres nouveaux agents anesthésiques devraient aussi être examinés quant à leurs effets électrographiques centraux durant leur évaluation comme addition possible à l’arsenal anesthésique.