Convulsive Phase Research Articles

Inhibition of seizures induced by picrotoxin and electroshock by cholecystokinin octapeptides and their fragments in rats after intracerebroventricular administration

The anticonvulsive activity of cholecystokinin octapeptide sulphate ester (CCK-8-SE), nonsulphated cholecystokinin octapeptide (CCK-8-NS) and three different N- and C-terminal fragments were investigated against seizures induced by picrotoxin and electroshock in rats after intracerebroventricular administration. Doses of 0.8 and 80 pmol of CCK-8-SE and CCK-8-NS significantly enhanced the latency of seizures induced by picrotoxin and shortened the duration of the clonic phase of the seizures induced by electroshock. Only CCK-8-SE shortened the recovery time and only 0.8 pmol of CCK-8-SE could shorten the duration of the tonic phase of convulsions induced by electroshock. Doses of the octapeptides of 8000 pmol were ineffective, with the exception of CCK-8-NS in the picrotoxin test. Of the fragments tested, the C-terminal tetrapeptide, CCK-5-8, enhanced the latency of seizures induced by picrotoxin in a dose of 0.8 pmol, and had a dose-dependent biphasic effect on the duration of the clonic phase of seizures induced by electroshock. Intracerebroventricular administration of diazepam enhanced only the latency of tremor and clonic seizures induced with picrotoxin in a dose of 40 nmol. Twelve nmole of diazepam shortened the clonic phase of convulsions induced by electroshock. The peptides tested were much more active than diazepam, and their effective doses were comparable to the amounts of cholecystokinin octapeptide found in brain structures.

Alterations in benzodiazepine and GABA receptor binding in rat brain following systemic injection of kainic acid

The binding of γ-aminobutyric acid (GABA) and benzodiazepine to receptors was examined in regions of rat brain at various times after subcutaneous injection of kainic acid (KA, 15 mg/kg). The animals exhibited pronounced convulsions 90 min–4 hr after this treatment. During this period (2 hr after the injection of kainic acid) no alterations in the binding of [ 3H]-GABA or [ 3H]flunitrazepam to receptors were detected in the frontal cortex, the hippocampus or the amygdala-pyriform cortex. After recovery from the acute convulsive phase, the rats appeared to be hyperexcitable, hyperactive, and displayed marked aggression and occasional clonic convulsions one to 80 days later. During this period a marked increase (80–200%) in the number of binding sites for GABA in the amygdala-pyriform cortex occurred but this was associated with a slow decrease in the number of binding sites for [ 3H]flunitrazepam to 70% control value at 3 weeks. Binding of the “peripheral” -type of benzodiazepine ligand, [ 3H]-Ro5-4864, was increased to 450% of control 3 weeks after injection. In addition, the ability of GABA to stimulate the binding of [ 3H]flunitrazepam was reduced when measured 3 days after the injection of kainic acid. It is suggested that the long-term behavioural syndrome observed in kainic acid-treated rats, as well as the reduced effectiveness of diazepam in preventing seizures in animals treated with kainic acid, (Czuczwar, Turski, Turski and Kleinrock, 1981) may be explained in part by a reduction in the number of neuronal benzodiazepine receptors and a “desensitization” of the GABA receptors which are coupled to benzodiazepine receptors.

Anticonvulsant effects of some inhibitory neurotransmitter amino acids.

The anticonvulsive effects of GABA, taurine, and glycine were investigated on several chemically-induced and genetic seizure models. Intravenous injections of either GABA, taurine, or glycine provided protection against 3-mercaptopropionic acid (MPA)-induced convulsions in adult Swiss mice. GABA was partially effective against isonicotinic acid hydrazide and was without effect against bicuculline-induced convulsions. Prolonged administration of glycine prevented MPA-induced convulsions but not electrically induced seizures or seizures induced by strychnine or metrazol. Intragastric glycine protected young audiogenic seizure-susceptible DBA/2 mice against all three phases of sound-induced convulsions (wild running, clonic and tonic seizure), but GABA and taurine provided little or no protection. With increase of glycine, the cerebral levels of glutamine and serine also increased, but that of glutamic acid decreased. The endogenous glutamic and glycine levels were slightly higher in the brains of the audiogenic seizure-susceptible DBA/2 mice than in that of the resistant BALB/Cy strain.

Pharmacological studies on neural mechanisms of clonic convulsions in mice: Action of cholinergic drugs.

In previous studies, we demonstrated that clonic seizures caused by either maximal electroshock or decapitation in mice were suppressed by intraspinal injection of 6-OHDA, suggesting that the induction of clonic seizures may be associated with spinal noradrenergic mechanisms. In the present study, we investigated whether clonic phase of maximal electroshock seizures (MES) and decapitation convulsions (DC) are also involved by drugs affecting cholinergic activity. Male adult mice (ddY) were used. MES were elicited with a current intensity through corneal electrodes (50 mA for 0.2 sec). Intensity of clonic seizures caused by a maximal electroshock and decapitation was recorded by an apparatus with an accelerometer. All drugs except bethanechol, carbachol and 6-OHDA were injected i.p.. Bethanechol, carbachol and 6-OHDA were administered into intrathecal space at Th8-L2 with a volume of 1 μl. The intensity of clonic seizures of MES and DC was suppressed by oxotremorine, physostigmine and bethanechol. Similarly, the clonic intensity of DC was reduced by carbachol, whereas it was enhanced by atropine and scopolamine. As previously shown, Phenytoin (PNT) increased the seizure intensity. Potentiating effects of PNT on clonic seizures of MES and DC were reduced by oxotremorine. The clonic intensity of MES was increased by methamphetamine and procaine. This increased intensity by these drugs was also reduced by oxotremorine. On the other hand, clonic seizure activity of DC which had been inhibited by 6-OHDA reappeared by atropine. These results suggest that cholinergic as well as noradrenergic neuronal activity in the spinal cord may play a role in causing clonic seizures of MES and DC in mice.

Dissociation between behavioral and electrocortical manifestations of electroshock convulsions during the action of an anticonvulsive drug

It was shown that 5-OH-5-ethyl-5-phenyl-butiramide (formerly called 5-ethyl-5-phenyl-2-pyrrolidinone) significantly reduces convulsions induced by electroshock in rats, and by drugs in mice. We are reporting a dissociation between the effects of this drug on the behavioral manifestations of electroshock and on the electrocortical afterdischarges. At 50 mg/kg, the drug reduced greatly the duration of the tonic phase of muscular convulsions, but had little or no effect on their total duration or on the electrocortical afterdischarges. At 100–150 mg/kg, the effect on the tonic phase was only slightly larger, but the total duration of behavioral convulsions and the intensity of electrocortical afterdischarges were substantially reduced, while the duration of the latter was either slightly reduced or increased. Only 200 mg/kg, which had clear depressant effects, produced a complete disappearance of all manifestations of electroshock convulsions. It can be concluded that this drug acts more strongly on subcortical structures that transmit cortical convulsions to the muscles, than on the cortical mechanisms that generate electrocortical afterdischarges.

The role of monoamines in the behavioural effects of kainic acid in rats.

Male albino rats given as intraperitoneal injection of kainic acid (11 mg/kg) showed a behavioural syndrome of wet-dog shakes, vertical paddling and tonic convulsions followed by aphagia and aggressivity. The phase of wet-dog shakes, vertical paddling and convulsions was reduced by pretreatment with benserazide and alpha-methylparatyrosine at low doses, while FLA-63 and high doses at AMPT (greater than 200 mg/kg) were toxic together with kainic acid. The phase of aphagia was not influenced reliably by any of the pretreatments, while the phase of aggressivity was potentiated strongly by parachlorophenylalanine and slightly by reserpine and AMPT. The findings suggest that dopaminergic and serotoninergic functions play a role in effects of kainic acid on behaviour in rats.

Two classes of pyrethroid action in the cockroach

Pyrethroids are divided into two classes (Types I and II) based on their effects on the cercal sensory nerves recorded in vivo and in vitro and on the symptomology they produce in dosed cockroaches, Periplaneta americana. Type I compounds include pyrethrins, S-bioallethrin, [1 R,cis]resmethrin, kadethrin, the 1 R,trans and 1 R,cis isomers of tetramethrin, phenothrin, and permethrin, and an oxime O-phenoxybenzyl ether. Electrophysiological recordings from dosed individuals reveal trains of cercal sensory spikes and sometimes also spike trains from the cercal motor nerves and in the CNS. Low concentrations of these pyrethroids act in vitro to induce repetitive firing in a cercal sensory nerve following a single electrical stimulus. This in vitro measurement, standardized for evaluating structure-activity relationships, shows that only 1 R, insecticidal isomers are highly effective neurotoxins. The most potent compounds on the isolated nerve are [1 R,trans]- and [1 R,cis]tetramethrin, each active at 3 × 10 −13 M. The poisoning symptoms of Type I compounds are restlessness, incoordination, hyperactivity, prostration, and paralysis. Type II compounds include [1 R,cis,α S]- and [1 R,trans,α S]cypermethrin, deltamethrin, and [ S,S]fenvalerate. These α-cyanophenoxybenzyl pyrethroids do not induce repetitive firing in the cercal sensory nerves either in vivo or in vitro; moreover, they cause different symptoms, including a pronounced convulsive phase. Two other pyrethroids with an α-cyano substituent, i.e., fenpropathrin and an oxime O-α-cyanophenoxybenzyl ether, are classified as Type I based on their action on a cercal sensory nerve but the symptoms with these compounds resemble Type II. The two classes of pyrethroid action evident with the cockroach are discussed relative to their neurophysiological effects and symptomology in other organisms.

Cyclic GMP and cyclic AMP in the cerebral cortex of mice during seizures induced by 3-mercaptopropionic acid: effects of anticonvulsant agents

The onset of clonic seizures induced by 3-mercaptopropionic acid (MP) was associated with an approximately 200% increase of cAMP and a 70% elevation of cGMP in the mouse both nucleotides during the subsequent tonic phase of convulsion; cAMP levels reached 400% and cGMP levels 300% of control values. The levels of both nucleotides did not differ from the controls 20 min after the termination of tonic seizures. When MP convulsions were prevented by Na-phenobarbital, the levels of both nucleotides were not different from control concentrations. Phenytoin prevented the tonic extension, but did not affect the clonic seizures. The accumulation of cAMP was markedly reduced (a residual + 40%), whereas the increased levels of cGMP remained unaffected.

Adaptation to high hydrostatic pressures of abyssal gammarids from Lake Baikal in Eastern Siberia

1. 1. Compression of freshwater gammarids from Lake Baikal elicits a series of 9 distinguishable response stages reflecting successive phases of hyperactivity, convulsions and immobilization. 2. 2. Convulsion threshold pressures are much greater for abyssal than for shallow water gammarids and average at a pressure near the maximum existing in the lake. 3. 3. Threshold pressures for the other two phases are substantially greater than can possibly be encountered in Lake Baikal and differ little between deep and shallow water gammarids. 4. 4. The relation of these observations to the problem of the role of hydrostatic pressure as a selection factor in the evolution of deep water fauna is discussed.

Effect of portacaval anastomosis on the toxicity of drug-induced convulsions in rats

End-to-side portacaval anastomosis (PCA) was performed in adult male Sprague—Dawley rats. Pentylenetetrazole (PTZ), picrotoxin (PCT), semicarbazide (SCZ), strychnine (STR) and amine-oxyacetic acid (AOAA) were administered parenterally. Time of onset of convulsive phase, duration of the convulsions and mortality were recorded. Time of onset of convulsions was significantly increased in rats with SCZ and was reduced with STR and PCT. Duration of convulsions was significantly increased by PTZ and SCZ and reduced by STR. AOAA blocked the SCZ-induced convulsions. Mortality was increased with PCT. It is suggested that PCA modifies the time of onset and duration of drug-induced convulsions.

Effects of intraventricularly administered monoamines on seizure susceptibility and body temperature in rats

Rats injected through permanent intraventricular cannulas with 8 μg of norepinephrine, 32 μg of dopamine or 8 μg of serotonin were tested 5 min later by the measurement of the electroshock seizure threshold and the duration of various components of tonic-clonic seizures induced electrically or with flurothyl. Each of the monoamines decreased the threshold for the minimal seizure and increased the duration of the tonic extension and postictal depression phases of maximal electroshock convulsions. The findings with flurothyl were less consistent among the monoamines, but decreased latencies for the myoclonic jerk and generalized convulsions and prolonged recovery from the seizure were observed. With the doses used all the monoamines produced hypothermia. In animals supplied with sufficient external heat to prevent hypothermia, the decreased electroshock seizure threshold was returned to normal. These findings indicate that the seizure-facilitating effects of intraventricularly administered monoamines are attributable to decreased body temperature.

The effect of 5,6-dihydroxytryptamine on post-decapitation convulsions

Previous data (1) have shown that L-DOPA increases the duration of the clonic phase of post-decapitation convulsions (PDC) in mice. It was suggested that this effect is produced by depleting 5-hydroxytryptamine (5-HT) in the inhibitory bulbospinal pathways and thus enhancing reflex activity in the spinal cord. If this were true then L-DOPA administration should not influence clonic PDC in animals whose 5-HT pathways were destroyed. We therefore tested the effects of L-DOPA on mice 3 weeks after pretreatment with the 5-HT neurotoxin, 5,6-dihydroxytryptamine (5, 6-DHT) (50 μg/kg, intracerebroventricularly). All mice were given the peripheral decarboxylase inhibitor, Ro 4-4602. 5,6-DHT halved the brain 5-HT levels and significantly increased the duration of clonic PDC. The administration of L-DOPA (320 mg/kg i.p.) to 5,6 DHT treated mice did not produce any further significant increases in duration. The administration of 5-hydroxytryptophan (5-HTP) (100 mg/kg, i.v.) to 5,6-DHT treated mice, however, increased 5-HT to above control levels and reduced convulsions to control levels. Administration of both 5-HTP and L-DOPA to 5,6-DHT treated mice resulted in 5-HT levels and convulsion times which were also not significantly different from the controls. These data give additional indication that intact 5-HT nerve terminals are necessary for L-DOPA to prolong the duration of clonic PDC.

EEG Patterns of Grand Mal Seizures Occurring Under Different Recording Conditions

SUMMARYThirty‐five EEG patterns of grand mal seizures recorded under some conditions such as awake‐rest, sleep activation, beme‐gride activation and intermittent photic stimulation were studied in 31 epileptics and four non‐epileptics.Preictal EEG's were generally variable in comparison with ictal EEG's. It was not till 10 sec before seizures that the incidence of seizure discharges changed in most all cases, of which six increased and four decreased.A paroxysmal extreme varied EEG abnormality often continued for several to several ten sec immediately before a tonic phase, associated with some clinical symptoms. EEG patterns of the “preconvulsive phase” were divided into six types with different clinical features. In most all cases of bamegride activation, poly‐spike and wave discharges preceded on seizure activities and some of them related with absence or psychomotor epilepsies. In all cases of sleep activation and photic stimulation, high voltage slow bursts or poly spikes preceded. Seizure patterns recorded at awake‐rest were indefinite. A few cases didn't show any preconvulsive EEG changes, and were closely related with grand mal epilepsies.While the grand mal seizure during sleep had a long tonic‐clonic convulsive phase and a short pre‐ and postconvulsive phase, that induced by bemegride activation showed the opposite findings. The grand mal seizure at awake‐rest had the middle tendency between the two.The differences among the effects of various recording conditions on seizure patterns present some suggestions as to the patho‐physiological mechanism of epileptic seizures.

The role of dopamine and serotonin in the prolongation of post-decapitation convulsions in mice

L-DOPA (320 mg/kg, i.p.) increased the duration of the clonic phase of post-decapitation convulsions (PDC) by 60% in mice pretreated with the peripheral decarboxylase inhibitor, Ro 4-4602 (50 mg/kg, i.p.). Assays of brains at the time of decapitation showed a 300% increase in dopamine (DM), an 80% reduction in serotonin (5-HT) and no change in norepinephrine (NE) levels. The effect of L-DOPA on PDC was not blocked by haloperidol (0.5 – 5.0 mg/kg), a blocker of DM receptors, nor by diethyldithiocarbamate (400 mg/kg) an inhibitor of NE synthesis. Parachlorophenylalanine (300 mg/kg × 3 days) produced an 80% reduction in 5-HT and a prolongation of PDC similar to that observed after L-DOPA. Prolongation of PDC was also seen after the 5-HT antagonists methysergide (5 mg/kg) and cinanserin (10 mg/kg), but not after cyproheptadine (10 mg/kg). The 5-HT precursor, 5-hydroxytryptophan (100 mg/kg), produced no change in PDC when used alone but inhibited L-DOPA's prolongation of PDC. The results suggest that L-DOPA acts by depleting 5-HT in bulbospinal pathways and thus enhancing reflex activity in the spinal cord.

Membrane Na, K-ATPase and acetylcholinesterase activity of the brain and spinal cord of rats during seizures

Activity of ATPases and acetylcholinesterase (ACE) in the fractions of unpurified mitochondria (UMF) and microsomes from the cortex of the brain and spinal cord of rats in the clonic phase of electrically induced seizures and in the postconvulsive period (5 min after the end of the seizures) was investigated. Inhibition of Na, K-ATPase activity in UMF of the brain in the clonic phase of convulsions and increased activity of this enzyme in all fractions of tissues studied in the postconvulsive period were found. Activity of Ca-ATPase in brain UMF increased during seizures but fell in the postconvulsive period, whereas activity of Mg-ATPase was unchanged. ACE activity as a rule increased during seizures; in the postconvulsive period a further increase in ACE activity was observed in the brain tissue but the activation effect was reduced in the spinal cord tissue. The possibility of structural changes in the excitable membranes of neurons during seizure activity is discussed.

Energy metabolism of mouse cerebral cortex during homocysteine convulsions

Convulsions were induced in mice by the intraperitoneal injection of dl-homocysteine thiolactone HCl. Energy metabolism of the cerebral cortex was studied during both the clonic and tonic phases of convulsions, and 5 min after the main seizure attack. During both phases of convulsions a decreased level of P-creatine, ATP and glycogen, an unchanged level of glucose and an increased level of lactate, ADP and AMP were observed. The energy charge potential of the adenine nucleotide pool (ECP) was lowered. Since the accumulation of lactate was higher than could be accounted for by the decrease of glycogen, an approximately 3–5-fold increase of glucose uptake from blood has to be assumed. After 5 min of recovery, partial restoration of lactate and glycogen, increased levels of P-creatine and glucose and normal values of ECP were observed; the energy balance of the tissue was again re-established. During the preparoxysmal period only a slight increase of glucose was observed; the other metabolites studied were normal. Clinical manifestations of homocysteine convulsions could be prevented by a non-anaesthetic dose of Na phenobarbital or by glycine. Metabolic changes were completely prevented by Na phenobarbital; in the case of glycine protection, a slight increase of lactate and a decrease of glycogen were observed. The present results have demonstrated that the changes in energy metabolism of brain during homocysteine convulsions differ substantially from those observed previously during seizures induced by methionine sulphoximine (MSO) 5,9. It therefore seems unlikely that homocysteine is an effective intermediary factor in MSO convulsions.

Biochemical effects of fluoroacetate administration in rat brain, heart and blood

Treatment of rats with fluoroacetate resulted in two phases of behaviour (i) a sedated phase followed by (ii) a tonic extensor convulsive phase. The levels of various labile metabolites such as citric acid, lactic acid, ammonia, free glucose and glycogen, were measured at these two phases in heart, brain and blood. In heart the citric acid level rose in both of the phases, however in brain the level of this metabolite fell at the convulsion following an initial rise during the sedative phase. This alteration in the citrate content of brain could have profound effects on the tricarboxylic acid cycle as a whole and also on the level of compounds, such as GABA, related to the cycle. The implications of such alterations on the overall behavioural patterns are discussed.

Memory and the extensor phase of convulsions induced by electroconvulsive shock

In Experiment 1, rats receiving electroconvulsive shock immediately following one-trial passive avoidance training displayed less amnesia on a 24-h retention test when the convulsion lacked a phase of hindlimb tonic extension. Experiment 2 found that attenuated amnesia and incomplete convulsions following electroconvulsive shock occurred in fewer animals on deprivation than on ad lib diets. However, deprivation did not appear to affect degree of amnesia in those animals exhibiting complete grand mal convulsions. These results suggest that future ECS research on memory can circumvent the problem of incomplete convulsions by using either young animals or adults on weight-limiting diets.

X-Ray Dose and Electroconvulsive Responses in Adult Rats

Electroshock seizure responses were studied in control and irradiated adult male rats exposed to single whole-body x-ray doses of 15, 20, 25, 50, 100, 250, and 500 r. Irradiation at all dose levels produced a statistically significant, dose-dependent reduction in threshold for electroshock seizures which lasted 2 to 3 weeks after 15 or 20 r, 2 to 3 months after 25 to 250 r, and more than 8 months after 500 r. Although body weight was decreased temporarily (after 25to 250 r) or permanently (after 500 r) in some of the irradiated rats, the magnitude, duration, and dosedependency of the reduction in threshold appeared to vary independently of changes in body weight. Alterations in the pattern of maximal electroshock seizures occurred onlv after doses of 50 r or more and lasted generally for the entire experimental method even after the lower effective doses; they consisted of a shortening of the duration of clonus and total seizure after 50 to 500 r and a lengthening of tonic extension with shoitening of tonic flexion after 500 r. The data are tentatively interpreted to indicate that whole-body x irradiation in doses of 15 to 500 r increases brain excitability as measured by loweringmore » of seizure threshold and by facilitation of tonic convulsive phases; induces an earlier than normal onset of neuronal fatigue as shown by shorter durations of clonus and total seizure; and affects various parameters of brain activity to a different degree, suggesting a differential radiosensitivity of specific regions and functions of the central nervous system.« less

INTRAOCULAR PRESSURE IN ELECTROCONVULSIVE THERAPY.

Investigations made hitherto indicate that a temporary rise in the intraocular pressure occurs during electroconvulsive therapy (ECT). Thus measurements made<i>during</i>the convulsive phase, which are rare since they assume a satisfactory degree of muscular relaxation, have shown an increase in tension.^13,18Measurements<i>after</i>the seizure have shown both a rise^1,10,11,14and a drop in tension.^3,16,17The contradictory results are probably due partly to the fact that the time for the measurements varied after the seizure²and partly to whether the muscular component of the seizure was relaxed or not.¹² The purpose of the present investigation was to study, under the conditions provided by modern treatment technique,⁸the intraocular pressure before, during, and shortly after the seizure and to study whether, with simple modifications of treatment, the increase of tension can be partly prevented. These problems were actualized for us when we were faced