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Core mechanisms in generalized convulsions.

A hypothetical model is proposed to account for the generalized convulsions observed in rats. Two versions of the hypothesis are discussed: an earlier, more specific formulation that accounts for kindled convulsions, and a later, general version that applies to generalized convulsions as a whole. Observations leading to the specific formulation of the model included: 1) kindling data that suggested a single downstream center responsible for kindled convulsions; 2) brain-stem stimulation data that indicated that the reticular core of that structure could initiate and maintain generalized convulsive behavior; and 3) spinal hemisection data that indicated that nonspecific systems in the cord could also maintain convulsions, even in the absence of direct input from the brain. The more specific version of the model suggests that kindled convulsions are nonspecific core seizures that occur when self-sustained epileptic activation spreads from forebrain foci to involve descending polysynaptic pathways in the nonspecific core of the brain stem and cord. Observations leading to a more general formulation of the model include the facts that: 1) maximal and submaximal convulsions in a variety of models resemble each other; and 2) they also resemble the maximal and submaximal seizures produced by direct stimulation of the brain stem and cord. The more general formulation of the nonspecific core hypothesis suggests that a wide variety of convulsions in rats may be nonspecific core seizures, differences in tonic-clonic and rostrocaudal configuration being related primarily to differences in the intensity of core activation.

Animals↗

Characterization of convulsions induced by methyl beta-carboline-3-carboxylate in mice.

The convulsive properties of methyl beta-carboline-3-carboxylate (beta-CCM) were evaluated in mice. When injected subcutaneously at a dose of 10 mg/kg beta-CCM induced convulsions in 75% of the mice with a median latency of 2.12 +/- 0.25 min. The CD50 was determined to be about 5 mg/kg. Electroencephalographic recordings showed that convulsions were brief (10 s), of cortical origin and propagating rapidly to the hippocampus. EEG alterations induced by low doses of beta-CCM lasted up to 1 h. The convulsive effect of beta-CCM was compared to that of PTZ. PTZ-induced convulsions occurred with a longer latency (9.26 +/- 1.33 min). beta-CCM and PTZ could act synergistically when injected in non-convulsive doses. When beta-CCM was injected 2-30 min before pentylenetetrazol (PTZ) there was a clear potentiation of the convulsive effect of PTZ. The convulsions induced by beta-CCM were blocked by diazepam (DZ) and by Ro 15-1788. In addition, beta-CCM reversed the sedative effect of a high dose of DZ for more than 30 min. Our results confirm that beta-CCM acts through the BZ receptor and indicate that the effects induced by a single dose of beta-CCM last more than 30 min.

Animals↗

"Peripheral-type" binding sites for benzodiazepines in brain: relationship to the convulsant actions of Ro 5-4864.

Previous studies have shown that Ro 5-4864 is a potent convulsant and increases the firing rate of substantia nigra zona reticulata neurons. The pharmacologic profile of compounds that antagonize these actions suggested that the effects of Ro 5-4864 were not mediated by "brain-type" benzodiazepine receptors. We examined a number of compounds that are structurally related to Ro 5-4864 for their capacities to displace [3H]Ro 5-4864 from "peripheral-type" binding sites and their potencies as convulsants (or as antagonists of Ro 5-4864-induced convulsions). It was observed that compounds such as KW 3600 (the N-desmethyl analog of Ro 5-4864), which have very low affinities for "peripheral-type" sites, are convulsants with a potency nearly equal to that of Ro 5-4864. In contrast, compounds such as Ro 5-6900 and PK 11195, which bind with very high affinities to "peripheral-type" binding sites, are neither convulsants nor do they antagonize the convulsant actions of Ro 5-4864. Within a series of compounds that are structurally related to Ro 5-4864 there is a good correlation (r = 0.93; p less than 0.01) between their potencies as convulsants and their capacities to displace [35S]t-butylbicyclophosphorothionate from sites that may be associated with the chloride ionophore. Thus, it appears that occupation of "peripheral-type" binding sites by high-affinity ligands may not be directly involved in the convulsant actions of Ro 5-4864 and related compounds.

Animals↗

[Drug interactions between nonsteroidal anti-inflammatory drug and pazufloxacin mesilate, a new quinolone antibacterial agent for intravenous use: convulsions in mice after intravenous or intracerebroventricular administration].

Convulsant activity of pazufloxacin mesilate (PZFX mesilate), a new quinolone antibacterial agent for intravenous use, in combination with nonsteroidal anti-inflammatory drug (NSAID) was investigated in mice after intravenous or intracerebroventricular administration. Following results were obtained. 1. In combination with 4-biphenylacetic acid (BPAA) at an oral dose of 100 mg/kg, PZFX mesilate did not induce any convulsions at intravenous doses up to 200 mg/kg. Reference quinolones induced convulsions at the following intravenous doses: Enoxacin (ENX), 3.13 mg/kg or more; norfloxacin (NFLX) and lomefloxacin (LFLX), 6.25 mg/kg or more; ciprofloxacin (CPFX), 50 mg/kg or more; sparfloxacin (SPFX) and temafloxacin (TMFX), 100 mg/kg or more; fleroxacin (FLRX), 200 mg/kg. 2. PZFX mesilate at an intravenous dose of 50 mg/kg did not induce convulsions in mice after oral administration of any of 14 kinds of NSAIDs. It induced convulsions at 200 mg/kg in combination with aspirin at an oral dose of 600 mg/kg, while it did not with the other 13 kinds of NSAIDs. 3. Convulsion-inducing dose of PZFX mesilate after intracerebroventricular administration was 100 mg/body, which was higher than those of reference quinolones (NFLX, CPFX, ENX, LFLX, TMFX, levofloxacin, ofloxacin, FLRX and SPFX) and beta-lactam antibiotics (penicillin G, cefazoline, imipenem/cilastatin and panipenem/betamipron). In addition, concurrent dosing of BPAA (1 microgram/body) did not reduce the convulsion-inducing dose of PZFX mesilate. These results suggest that PZFX mesilate has remarkably weak convulsant activity.

Administration, Oral↗

[Characterization of an experimental model of monosodium- glutamate-induced convulsions in the amphibian Bufo spp].

In previous reports, Feria-Velasco et al. characterized an experimental model of convulsions in rats induced by monosodium glutamate (MSG) with evaluation of the motor behavior and neurochemical parameters. In the present work, MSG injected in toads (Bufo spp) reproduced the model of convulsions with some peculiarities. The electrocorticographic recordings in toads after MSG injection were similar to those obtained in rats after administration of convulsant agents. Most of the toads injected with MSG (81.8%) showed convulsions preceded by an episode of stereotyped movements and signs of hyperexcitability. Latency for convulsions and frequency of convulsive episodes were similar to what has been reported in rats injected with MSG. However, the duration of convulsive period was larger than that seen in rats, and no deaths were recorded in toads. The peculiar feature of amphibia regarding their cerebral structures and their blood-brain barrier (BBB) make the amphibian model, an interesting and valuable one in studying experimentally induced convulsions, as well as the role of BBB in these phenomena.

Animals↗

Mechanisms of sensory seizures: brain-stem neuronal response changes and convulsant drugs.

Generalized convulsive seizures can be triggered by sensory stimuli in animals treated with subthreshold levels of convulsant drugs. The sensory responses of the brain-stem reticular formation (RF) are extensively enhanced before seizure initiation with bicuculline, strychnine, pentylenetetrazol, physostigmine, and several other convulsants. The responses of RF neurons are more greatly enhanced than other nonprimary neurons in the hippocampus, amygdala, and cortex. The action of systemically administered convulsants involves direct effects on reticular neurons, because RF response enhancement is also seen with iontophoresis. RF neuronal response enhancement does not appear to involve actions of convulsants on specific neurotransmitters, because agents that act on different transmitters enhance the responses of the same RF neuron when given sequentially. Anticonvulsant drugs reverse the effects of convulsants on reticular neurons. The convulsant-induced response enhancement in the RF may involve blockade of inhibitory postsynaptic potentials and/or threshold reduction, effects observed in vitro. RF neurons may be most susceptible to convulsant action because these agents block habituation and other mechanisms that normally restrict RF neuronal responsiveness. The massive synchronization of reticular neuronal firing by sensory stimuli may induce seizures by intense output over widespread RF projection pathways analogous to the afterdischarge seizures seen with electrical stimulation of the RF.

Animals↗

Sustained effects of pilocarpine-induced convulsions on brain inositol and inositol monophosphate levels and brain morphology in young and old male rats.

Cerebral inositol and inositol monophosphates, products of phosphoinositide (PI) turnover, and neuronal injury were studied in young (10 weeks) and old (24 months) male Wistar rats after pilocarpine-induced convulsions. The goal was to explore the association between short-term cholinergic convulsions, brain PI signaling, and changes in the brain morphology in the young and the old rats. Pilocarpine caused convulsions in young rats at a dose of 300 mg/kg, whereas a dose of 175 mg/kg was required to obtain the same effect in old rats. A dose of 5 mg/kg of diazepam was used to terminate the convulsions 2 hr after their initiation; the rats were then examined on Day 5 postpilocarpine. Inositol and inositol monophosphate levels were similar in both the young and the old control rats. Pilocarpine-induced convulsions decreased cerebral inositol and increased inositol-1-phosphate in both the young and the old rats. Inositol-4-phosphate was stable in the young rats but increased in the frontal cortex and the hippocampus in the old rats. Delayed neuronal death also occurred in the convulsing rats, i.e., a variable proportion of neurons appeared shrunken with eosinophilic cytoplasm and pyknotic nuclei. The hippocampus was the most severely affected brain area. These results show that old rats are more sensitive than young ones to short-term pilocarpine convulsions, associated with sustained PI turnover, and brain injury. Mechanisms in addition to cholinergic ones are likely to be involved in the prolonged cerebral effects of cholinergic convulsions in rats.

Aging↗

Histamine levels and clonic convulsions of electrically-induced seizure in mice: the effects of alpha-fluoromethylhistidine and metoprine.

The purpose of this study was to investigate the possible role of the central histaminergic neuron system in electrically-induced seizure in mice. For this purpose, we examined the effects of intraperitoneal (i.p.) injections of histaminergic agents, such as L-histidine, metoprine, and alpha-fluoromethylhistidine (FMH), on electrically-induced seizure. L-Histidine decreased the duration of clonic convulsion in electrically-induced seizure, but not affected that of tonic convulsion. This effect of L-histidine was antagonized by pretreatment with FMH, indicating that it was due to histamine formed by decarboxylation of L-histidine in the central nervous system. The anticonvulsive effect of L-histidine was also reduced by the H1-antagonist pyrilamine, but not by the H2-antagonist zolantidine, indicating that the effect on electrically-induced seizure is mediated through central H1-receptors. Metoprine, which increased the histamine levels in the cerebral cortex, diencephalon and midbrain of mice, decreased the duration of clonic convulsions dose-dependently. Conversely, FMH, which decreased the brain histamine levels, increased the duration of clonic convulsions. Good inverse correlations were found between the duration of clonic convulsions and brain histamine levels, especially in the diencephalon: the histamine levels were inversely proportional to the duration of clonic convulsions. No correlation was found between the duration of tonic convulsions and brain histamine levels. These results suggest that the histaminergic neuron system is important in inhibition of the duration of clonic convulsion on electrically induced seizure in mice.

Animals↗

Differential effects of flurothyl- and electro-convulsive shock on sexual maturation and prolactin release in the rat.

The effects of single and repeated seizures on luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin secretion and on the onset of sexual maturation in rats are described. In addition, the influence of convulsions generated electrically (electroconvulsive shock, ECS) and chemically (using flurothyl) are compared. Repeated flurothyl convulsions and ECS (one daily convulsion from age 24 days) significantly delay vaginal opening in female rats. The incidence of first ovulation at maturation is reduced to 20% compared with 70-100% for untreated groups. Body and adrenal weights in immature rats are not modified by flurothyl convulsions. Repeated ECS does not influence adrenal weight although somatic growth is inhibited. In an effort to clarify the mechanism of action of convulsions on puberty onset, we examined acute changes in LH, FSH and prolactin secretion and the surge response of LH/FSH to gonadal steroid priming. A single flurothyl convulsion potently inhibits prolactin secretion. In contrast, an ECS acutely stimulates prolactin release in male and female rats. Convulsive seizures do not consistently alter tonic gonadotropin output. However, both flurothyl convulsions and ECS attenuate estradiol benzoate/progesterone-induced LH and FSH surges in ovariectomized rats though this is apparently not mediated by dopamine/prolactin since bromocriptine treatment delays sexual maturation without preventing ovulation at first estrus. Similarly, bromocriptine does not disrupt LH/FSH surges induced by gonadal steroid treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Convulsions induced by hyperbaric oxygen: inhibition by phenobarbital, diazepam and baclofen.

1. The anticonvulsive potencies of diazepam, phenobarbital and baclofen against convulsions induced by oxygen under high pressure (OHP), by isoniazid and by strychnine were investigated in mice and rats. 2. The anticonvulsive potency of diazepam was much higher than that of phenobarbital and baclofen against all three types of convulsions. 3. The selective activity of diazepam against isoniazid induced convulsions in rats (dose ratio ED50 phenobarbital/ED50 diazepam: 400) could not be confirmed in mice (dose ratio ED50 phenobarbital/ED50 diazepam: 20-40), where diazepam was equipotent against all three types of convulsions. 4. Baclofen which does not inhibit strychnine induced convulsions was equipotent in inhibiting convulsions evoked by isoniazid and OHP in mice. 5. The results are in agreement with the postulated GABA-inhibitory mechanism of OHP induced convulsions, whereas they make a glycine inhibitory mechanism very unlikely. Although the results do not allow further conclusions about the mode of action of diazepam, a clinical trial of diazepam in OHP-induced convulsions should be considered.

Aminobutyrates↗

Separation of the convulsions and antidepressant-like effects produced by the delta-opioid agonist SNC80 in rats.

RATIONALE: Delta-opioid agonists produce a number of behavioral effects, including convulsions, antinociception, locomotor stimulation, and antidepressant-like effects. The development of these compounds as treatments for depression is limited by their convulsive effects. Therefore, determining how to separate the convulsive and antidepressant-like characteristics of these compounds is essential for their potential clinical use. OBJECTIVE: The present study tests the hypothesis that the rate of delta-opioid agonist administration greatly contributes to the convulsive properties, but not the antidepressant-like effects, of delta-opioid agonists. MATERIALS AND METHODS: The delta-opioid agonist SNC80 (1, 3.2, and 10 mg kg-1 or vehicle) was administered to Sprague-Dawley rats by intravenous infusion over different durations of time (20 s, 20, or 60 min). Convulsions were measured by observation prior to determining antidepressant-like effects in the forced swim test. RESULTS: Slowing the rate of SNC80 administration minimized delta agonist-induced convulsions without altering the effects of SNC80 in the forced swim test. CONCLUSIONS: These data suggest that delta agonist-induced antidepressant properties are independent of convulsive effects, and that it may be possible to eliminate the convulsions produced by delta agonists, further promoting their potential clinical utility.

Analysis of Variance↗

Serotonin(2C) receptors appear to mediate genetic sensitivity to cocaine-induced convulsions.

RATIONALE: C57BL/6ByJ (6ByJ) and C57BL/6J (6J) mice differ in their sensitivity to cocaine-induced convulsions, with CD(50) values being 100 and 70 mg/kg, respectively. This genetic sensitivity to cocaine-induced convulsions is probably related to 5-HT(2) receptors, since the density of these sites and the concentration of 5-HT(2) antagonists required to block cocaine-induced convulsions is lower in 6J mice relative to 6ByJ mice. OBJECTIVE: Although 5-HT(2) receptors appear to play a role in mediating genetic sensitivity to cocaine-induced convulsions, the role of 5-HT(2) receptor subtypes in this effect of cocaine has not been examined. METHODS: The present study compared the effects of the preferential 5-HT(2C) agonists m-chlorophenylpiperazine (mCPP) and 6-chloro-2-(1-piperazinyl)pyrazine (MK212) on cocaine-induced convulsions in 6ByJ and 6J mice. General activity was also measured following pretreatment with mCPP and MK212. RESULTS: Both mCPP and MK212 potentiated cocaine-induced convulsions and the effect of these agonists was more robust in 6ByJ mice relative to 6J mice. CONCLUSION: The findings from this study support previous research suggesting that 5-HT(2) receptors play a role in mediating cocaine-induced convulsions, and extend previous research by suggesting that the 5-HT(2C) receptor subtype mediates cocaine-induced convulsions and genetic sensitivity to this toxic effect of cocaine.

Animals↗

The effects of repeated audiogenic convulsions on the organization of sleep in rats.

The organization of sleep in Krushinskii-Molodkina rats, with an inherited predisposition to audiogenic convulsions, was studied during and after repeated audiogenic convulsions consisting of two, three, or five relatively rare (separated by intervals of 90 min) or three, five, or nine relatively frequent (separated by intervals of 45 min) generalized clonic-tonic convulsions. In rats subjected to repeated seizures with rare convulsions, behavior in the periods between individual convulsions was dominated by passive waking (75.2 +/- 4.6% of the time), with a low level (24.8 +/- 4.3%) of slow-wave and a complete absence of fast-wave sleep, i.e., there was selective removal of the fast-wave sleep phase from the sleep-waking cycle of the rats. In rats subjected to frequent seizures with frequent convulsions, the period between convulsions showed only passive waking, with complete loss of slow-wave and fast-wave sleep, i.e., total sleep deprivation took place. The minimal latent period before the appearance of the first episodes of slow-wave sleep after repeated convulsions was 59.9 +/- 10.8 min; that for fast-wave sleep was 158.2 +/- 13.4 min. However, the first episodes of slow-wave and fast-wave sleep had an essentially normal structure, though episodes shorter than those in controls were seen, albeit more rarely. Despite the prolonged (up to 7 h) absence of slow-wave sleep during seizures and the prolonged (8.5 h) decrease in fast-wave sleep, there was no compensatory increase in the levels of these states in the sleep-waking cycle during the 12 h of recovery after seizures. Overall, the recovery period after repeated seizures was characterized by an increase (compared with controls) in the total proportion of waking in the behavior of the rats, with a decrease in the total duration of slow-wave and fast-wave sleep. It is concluded that the paroxysmal status significantly disorganizes the operation of the sleep-generating structures of the brain. The functioning of the systems responsible for slow-wave sleep is less affected, while impairments of the activity of the systems responsible for the formation of fast-wave sleep are more significant, affecting primarily the mechanisms triggering this sleep phase.

Acoustic Stimulation↗

The role of locus coeruleus in decapitation convulsions of rats.

The role of the central norepinephrine (NE) system, especially the locus coeruleus (LC), in the occurrence of decapitation convulsions was investigated in rats. Intraspinal injection of 6-hydroxydopamine (6-OHDA) caused a significant inhibition of decapitation convulsions as shown by prolongation of the latency and shortening of the convulsion's duration, as well as decreasing the NE content of the spinal cord to 35% of the control value without affecting the NE content of the various regions in the brain. Chemical lesion of the descending bundle from the LC by treatment with 6-OHDA significantly inhibited decapitation convulsions in a similar manner. Moreover, there was a decrease in the NE content of the spinal cord and hypothalamus to 24% and 47% of the control value, respectively. Bilateral electrolytic lesion of the LC also significantly inhibited decapitation convulsions and decreased the NE content of the cortex and spinal cord to 15% and 74% of the control value, respectively. However, lesions of the dorsal and ventral NE bundle by treatment with 6-OHDA, which caused a marked decrease in the NE content of the cortex and hypothalamus, respectively, did not affect the decapitation convulsion. Intraspinal injection of 5,6-dihydroxytryptamine resulted in a decrease in the 5-hydroxytryptamine content of the spinal cord only; moreover, it did not change the decapitation convulsion. These results suggest that coeruleospinal NE neurons play an important role in the occurrence of decapitation convulsions.

5,6-Dihydroxytryptamine↗

Vasopressin may mediate febrile convulsions.

The possibility that arginine vasopressin (AVP) is involved in the etiology of febrile convulsions was investigated by experiments on hyperthermia-induced convulsions in rats. Homozygous Brattleboro rats, which genetically lack AVP, and Long Evans rats, which were passively immunized by intracerebroventricular anti-AVP antiserum, either convulsed at higher body temperatures than untreated Long Evans rats or did not convulse at all. This indicates that a lack of AVP increases the threshold for the convulsions. High blood levels of AVP in hyperthermic convulsing rats compared to hyperthermic non-convulsive rats support the hypothesis that AVP may mediate febrile convulsions.

Animals↗

Inhibition of post-decapitation convulsions in the rat by dibenzothiepin neuroleptics via alpha 1-adrenoceptor blockade.

The mechanisms involved in inhibitory effects of isofloxythepin, a newly synthesized dibenzothiepin neuroleptic, on post-decapitation convulsions were studied in rats. Isofloxythepin (0.05-2.0 mg/kg s.c.) inhibited post-decapitation convulsions in a dose-dependent manner as shown by the decrease in the incidence and the shortening of the duration of convulsions. The convulsions were also inhibited by oxyprothepin, zotepine or chlorpromazine but not by haloperidol. Prazosin and bunazosin, both alpha 1-adrenoceptor antagonists, suppressed the post-decapitation convulsions but a non-selective alpha 2-adrenoceptor agonist, tolazoline, was without effect. The convulsions were inhibited dose dependently by clonidine, an alpha 2-adrenoceptor agonist, but were prolonged in duration by yohimbine, an alpha 2-adrenoceptor antagonist. Yohimbine antagonized the inhibitory effects of isofloxythepin, prazosin and clonidine. The noradrenaline-induced contraction of rat vas deferens was inhibited by isofloxythepin, prazosin or chlorpromazine. Isofloxythepin bound to alpha 1-receptors as did chlorpromazine in the rat brain cortex. The results imply that post-decapitation convulsions seem to be inhibited by a block of postsynaptic alpha 1-adrenoceptors, enhanced by a block of presynaptic alpha 2-adrenoceptors and reduced by isofloxythepin via the blocking of postsynaptic alpha 1-adrenoceptors. The convulsions thus could serve as a good model for studying the actions of drugs on the central nervous system alpha-adrenoceptors.

Adrenergic alpha-Agonists↗

Cerebrospinal fluid folate and cobalamin levels in febrile convulsion.

Folate and cobalamin parameters were studied in the serum and cerebrospinal fluid of 40 febrile paediatric patients. Eighteen of these children were in a state of febrile convulsion while the remaining 22 were non-convulsing. The serum folate concentration of all the patients was higher than that of the control group but the highest value was found in the convulsing children. There was no significant difference in the CSF folate levels between the two groups of patients. The serum cobalamin levels of the patients were significantly lower than those of the control children and the lowest mean was observed in the convulsing state. On the other hand, there was no difference in the CSF cobalamin between the convulsing and non-convulsing children. These results confirm that there is an effective blood-brain barrier system for folate even when serum folate levels are higher than normal. There is also a definite decrease in serum cobalamin during pyrexia but this decrease is more apparent in the convulsing state. The role of cobalamin metabolism in convulsion is not clear.

Blood-Brain Barrier↗

Effects of central monoamine compounds on tranylcypromine-induced barbital-withdrawal convulsions.

Challenge with tranylcypromine (Tcp) during barbital (B) withdrawal induces dose-related clonic-tonic convulsion (C-TC), which is also related to the severity of withdrawal signs and their changes with the passage of time. The effects of neuropharmacological agents on the Tcp-induced convulsions were observed. dl-Propranolol, phentolamine, phenoxybenzamine and methysergide had been administered intraperitoneally 20 approximately 30 minutes before Tcp challenge. B-withdrawn rats had been pretreated with alpha-methyl-p-tyrosine, 5-hydroxytryptophan, p-chlorophenylalanine or reserpine, or with the combination of iproniazid and reserpine (5 hrs after iproniazid administration) before Tcp challenge. alpha-MT and dl-propranolol inhibited B withdrawal convulsion markedly, though high doses of dl-propranolol rather tended to show a less effect on the convulsion. alpha-Adrenoceptor blockers scarcely inhibited the convulsion. Methysergide or 5-HTP failed to inhibit, but PCPA intensified the convulsion. Reserpine, when administered alone, aggravated the convulsion, but when administered after iproniazid, inhibited it significantly. These findings suggested that the balance between the activities of noradrenergic and serotonergic neurons might be of importance in the manifestation of B withdrawal convulsions, the former probably being excitatory and the latter, inhibitory.

Animals↗