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PubMed2004

Convulsant and anticonvulsant effects of bupropion in mice.

This study demonstrated that bupropion hydrochloride, an effective antidepressant and a commonly used smoking cessation aid, dose-dependently caused clonic convulsions in mice, with the CD50 (convulsive dose50, i.e., the dose producing convulsions in 50% of mice) at 119.7 mg kg(-1). An evaluation for anticonvulsant effects showed that bupropion in the doses of 15-30 mg kg(-1) protected against convulsions induced by maximal electroshock with the ED50 (effective dose50, i.e., the dose protected 50% of mice against convulsions) being 19.4 mg kg(-1). Bupropion had no effect on pentylenetetrazole- and kainic acid-induced convulsions. It is possible that the anticonvulsant activity of bupropion may be exploited for use in the treatment of epilepsy but it requires further investigations.

Animals↗
PubMed2000

Effects of differential modulation of mu-, delta- and kappa-opioid systems on bicuculline-induced convulsions in the mouse.

The present study investigated the effects of micro-, delta- and kappa-opioid receptor agonists on seizures produced by blockade of gamma-aminobutyric acid (GABA)-mediated synaptic transmission in the mouse. The selective GABA(A) receptor antagonist bicuculline (1.25-3 mg/kg) given subcutaneously caused dose-dependent clonic-tonic convulsions. These convulsions were potentiated by the prototypic mu-opioid receptor agonist morphine given subcutaneously 20 min prior to a subconvulsive dose of bicuculline. The potentiation by morphine was completely reversed by pretreatment intraventricularly with the selective mu-opioid receptor antagonist beta-funaltrexamine (0.5 microgram/mouse). Pretreatment intraventricularly with the selective delta-opioid receptor agonists 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12abeta-octahydro-quinolino[2,3,3-g]isoquinoline ((-)TAN-67) or [D-Pen(2,5)]-enkephalin (DPDPE) showed a dose-dependent increase in the incidence of convulsions. Pretreatment with naltrindole (2 mg/kg, s.c.), a selective delta-opioid receptor antagonist, abolished the enhancement of the bicuculline-induced convulsions by DPDPE. In contrast, pretreatment with the selective kappa-opioid receptor agonist U-50,488H (0.6-80 mg/kg, subcutaneously or 25-100 microgram/mouse, intraventricularly) produced a dose-dependent suppression of the bicuculline-induced convulsions. The inhibitory effect of U-50,488H was completely blocked by pretreatment subcutaneously with nor-binaltorphimine (5 mg/kg), a selective kappa-opioid receptor antagonist. This study demonstrates that activation of both mu- and delta-opioid receptors increases the incidence of convulsions produced by blockade of GABA-mediated synaptic transmission, while stimulation of kappa-opioid receptors has an anticonvulsive effect.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1997

Convulsant activity of nonanesthetic gas combinations.

Most nonanesthetics (inhaled compounds that neither cause anesthesia when given alone nor decrease the partial pressure of a known inhaled anesthetic required to produce anesthesia) and transitional compounds (inhaled compounds that are less potent than would be predicted by the Meyer-Overton hypothesis) cause convulsions. A possible exception is the perfluoroalkane series of nonanesthetics. The present study tested whether perfluoroalkanes do provide an exception. Further, we tested whether the convulsant effects of nonanesthetic and transitional compounds were additive. The nonanesthetic perfluoropropane caused convulsions at 7.5 +/- 0.7 atm (mean +/- SD). Convulsions also were produced by perfluorocyclobutane (0.976 +/- 0.002 atm), 1,2-dichlorotetrafluoroethane (0.358 +/- 0.011 atm), 2,3-dichlorooctafluorobutane (0.085 +/- 0.007 atm), 1,2-dichlorohexafluorocyclobutane (0.055 +/- 0.007 atm), and flurothyl (0.00156 +/- 0.00039 atm). Of these, 1,2-dichlorotetrafluoroethane is a transitional compound, the remainder being nonanesthetics. The combination of flurothyl plus 1,2-dichlorohexafluorocyclobutane gave evidence of antagonism (a 17% +/- 21% deviation from additivity; P < 0.05), whereas the combination of 1,2-dichlorotetrafluoroethane plus 2,3-dichlorooctafluorobutane gave evidence of synergy (a -13% +/- 8% deviation from additivity; P < 0.05). The combinations of perfluoropropane plus perfluorocyclobutane (-4% +/- 15%), and perfluoropropane plus 1,2-dichlorohexafluorocyclobutane (-1% +/- 26%) did not produce results that deviated significantly from additivity. We conclude that pairs of these compounds either produce convulsions in an additive manner, a finding consistent with (but not proving) a common mode of action; or deviate modestly from additivity, a finding suggesting that at least a portion of the mechanistic basis for convulsions might differ, particularly for flurothyl plus other nonanesthetics, or for the combination of non-anesthetics and transitional compounds.

Animals↗
PubMed1999

Depressant and convulsant barbiturates both inhibit neuronal nicotinic acetylcholine receptors.

UNLABELLED: Neuronal nicotinic acetylcholine receptors (neuronal nAchRs) are sensitive to many anesthetics, including barbiturates, which suggests that these receptors are potential sites for anesthetic action. Subtle changes in molecular structures of the anesthetic barbiturates can produce compounds with potent convulsant activity. Whereas R(-) isomer of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) exerts anesthetic action, S(+)MPPB exhibits pure excitatory effects, including convulsion. 5-(2-cyclohexilidene-ethyl)-5-ethyl barbituric acid is another example of a convulsant barbiturate. We compared the effects of depressant and convulsant barbiturates on the neuronal nAchR-mediated current to determine whether inhibition of neuronal nAchRs contributes to the anesthetic action of barbiturates. Whole cell nicotine-induced currents were recorded in PC12 derived from rat pheochromocytoma, using the conventional whole cell patch clamp technique in the presence and absence of barbiturates. Both depressant and convulsant barbiturates inhibited the nicotine-induced inward current reversibly and in a dose-dependent manner when co-applied with nicotine. All barbiturates accelerated the current decay. There was no significant difference between the concentrations for 50% inhibition for MPPB isomers. There was no correlation between inhibition of ganglionic nAchRs and anesthetic effects of the barbiturates. These results strongly oppose the idea that inhibition of neuronal nAchRs contributes to the anesthetic action of barbiturates. IMPLICATIONS: We found that both convulsant and depressant barbiturates inhibit the current mediated through ganglionic nicotinic acetylcholine receptors in PC12 cells. This finding suggests that the inhibition of neuronal nicotinic acetylcholine receptors does not contribute to the anesthetic action of barbiturates.

Animals↗
PubMed2002

The relationship between hippocampal acetylcholine release and cholinergic convulsant sensitivity in withdrawal seizure-prone and withdrawal seizure-resistant selected mouse lines.

BACKGROUND: The septo-hippocampal cholinergic pathway has been implicated in epileptogenesis, and genetic factors influence the response to cholinergic agents, but limited data are available on cholinergic involvement in alcohol withdrawal severity. Thus, the relationship between cholinergic activity and responsiveness and alcohol withdrawal was investigated in a genetic animal model of ethanol withdrawal severity. METHODS: Cholinergic convulsant sensitivity was examined in alcohol-naïve Withdrawal Seizure-Prone (WSP) and-Resistant (WSR) mice. Animals were administered nicotine, carbachol, or neostigmine via timed tail vein infusion, and the latencies to onset of tremor and clonus were recorded and converted to threshold dose. We also used microdialysis to measure basal and potassium-stimulated acetylcholine (ACh) release in the CA1 region of the hippocampus. Potassium was applied by reverse dialysis twice, separated by 75 min. Hippocampal ACh also was measured during testing for handling-induced convulsions. RESULTS: Sensitivity to several convulsion endpoints induced by nicotine, carbachol, and neostigmine were significantly greater in WSR versus WSP mice. In microdialysis experiments, the lines did not differ in basal release of ACh, and 50 mM KCl increased ACh output in both lines of mice. However, the increase in release of ACh produced by the first application of KCl was 2-fold higher in WSP versus WSR mice. When hippocampal ACh was measured during testing for handling-induced convulsions, extracellular ACh was significantly elevated (192%) in WSP mice, but was nonsignificantly elevated (59%) in WSR mice. CONCLUSIONS: These results suggest that differences in cholinergic activity and postsynaptic sensitivity to cholinergic convulsants may be associated with ethanol withdrawal severity and implicate cholinergic mechanisms in alcohol withdrawal. Specifically, WSP mice may have lower sensitivity to cholinergic convulsants compared with WSR because of postsynaptic receptor desensitization brought on by higher activity of cholinergic neurons.

Acetylcholine↗
PubMed1985

Dissociation of [35S]t-butylbicyclophosphorothionate binding differentiates convulsant and depressant drugs that modulate GABAergic transmission.

The dissociation of [35S]t-butylbicyclophosphorothionate ([35S]TBPT) from binding sites on membranes from rat cerebral cortex, after addition of saturating concentrations of convulsant and depressant drugs, was studied. The addition of unlabeled TBPT, picrotoxinin, or pentamethylenetetrazol resulted in dissociation patterns that were monophasic and not distinguishable, suggesting that these convulsants bind competitively to the same (convulsant) sites. In contrast, gamma-aminobutyric acid (GABA) greatly facilitated [35S]TBPT dissociation by binding allosterically to the GABA recognition site of the receptor-ionophore complex. TBPT dissociation was similarly accelerated by the depressants etazolate, (+)-etomidate, and barbiturates. The convulsant and depressant S(+) and R(-) stereoisomers of N-methyl-5-phenyl-5-propyl-barbituric acid displayed large stereoselectivity in the acceleration of TBPT dissociation. These results suggest that depressants bind to sites different from the convulsant sites of the allosteric GABA receptor complex, or the binding of depressants to the same population of sites elicits negative cooperativity and dissociates the convulsants.

Animals↗
PubMed1982

Pharmacological investigation of convulsant gamma-aminobutyric acid (GABA) antagonists in amygdala-kindled rats.

The convulsant potencies of several drugs that antagonize GABAergic neurotransmission were assessed in amygdala-kindled and control rats. The potencies of picrotoxin, pentylenetetrazol, and a convulsant barbiturate were increased by amygdala kindling. No significant potentiation, however, was observed with isoniazid, 3-mercaptopropionic acid, bicuculline, or the glycine antagonist strychnine. Destruction, by electrolytic lesion, of the amygdala focus did not reverse the kindling-induced potentiation of picrotoxin convulsions. The potentiation of picrotoxin convulsions was correlated with the pattern of kindling development but not with the number of stimulations or seizures. The present results are consistent with the hypotheses that (1) kindling potentiates only some convulsant agents, (2) kindling-induced convulsant potentiation takes place outside of the kindled focus, and (3) kindling is not produced by a failure of the GABA system.

Amygdala↗
PubMed1998

The effects of convulsant and anticonvulsant treatments on the behavioural effects of ultrasound presentation in Lister hooded rats.

Lister hooded rats exhibit bursts of locomotion when exposed to a 20 kHz acoustic stimulus; this ultrasound-induced locomotion has been suggested as a potential model for panic attacks. The present studies determined the effects of treatment with the convulsant agents strychnine and pentylenetetrazole and the anticonvulsant agents pentobarbital and ethosuximide on locomotor behaviour elicited by experimenter-presented ultrasounds in Lister hooded rats. Behaviour in a circular arena was viewed live and tracked electronically. In Experiment 1, brief exposure to an ultrasound stimulus typically resulted in short intensity-related bursts of locomotion in control rats. Pentobarbital or ethosuximide treatment reduced this short-term ultrasound-induced locomotion in a dose-related manner, whereas pentylenetetrazole or strychnine treatment increased these locomotor bursts. In Experiment 2, exposure to the ultrasound stimulus for a longer period resulted in irregular cycles of bursts of locomotion followed by periods of relative inactivity in control rats. In addition, approximately 10% of control rats exhibited convulsions associated with this long-duration ultrasound exposure at 98 dB sound pressure level. Sub-convulsant doses of the convulsant treatments increased the frequency of occurrence of convulsions associated with the ultrasound stimulus; pentobarbital or ethosuximide pretreatment significantly reduced this effect. The present findings suggest that a relationship exists between ultrasound-induced locomotor bursts and convulsant activity.

Animals↗
PubMed2001

Effect of systemically administered nitric oxide donor, sodium nitroprusside on picrotoxin-induced convulsions in rats.

Nitric oxide (NO), the gaseous neurotransmitter has been reported to have an endogenous anticonvulsant property. This has prompted proposals to develop NO donors as anticonvulsant drugs. In the present study, the effect of NO donor, sodium nitroprusside (SNP) on picrotoxin (PCT)-induced convulsions was investigated. A convulsant dose of PCT (5 mg/kg) was administered 5, 10, 15 and 30 min after intraperitoneal injection of graded doses (0.7, 1.25 and 2.5 mg/kg) of SNP. SNP at doses 0.7 and 1.25 mg/kg increased dose dependently the severity of PCT-induced convulsions. But, pretreatment with the higher dose (2.5 mg/kg) of SNP was protective against PCT-induced convulsions. However, post treatment (5 and 10 min) with the same dose exacerbated convulsions and caused death of the animals. These results indicate that the vasodilator effect of SNP and an increased perfusion of PCT into brain may be responsible for the proconvulsant action of SNP. A decreased entry of PCT because of marked vasodilation and hypotension has been speculated for an inhibition of convulsions in animals pretreated with a higher dose of SNP. In conclusion, the results reveal the non-suitability of SNP to be developed as an anticonvulsant.

Animals↗
PubMed1978

Differential inhibition of glutamine and gamma-glutamylcysteine synthetases by alpha-alkyl analogs of methionine sulfoximine that induce convulsions.

The alpha-methyl and alpha-ethyl analogs of methionine sulfoximine, like methionine sulfoximine, induce convulsions in mice and inhibit glutamine synthetase irreversibly; alpha-ethylmethionine sulfoximine is approximately 50% as inhibitory as methionine sulfoximine and alpha-methylmethionine sulfoximine. However, whereas alpha-methylmethionine sulfoximine and methionine sulfoximine inhibit gamma-glutamylcysteine synthetase markedly, alpha-ethylmethionine sulfoximine does not, nor does administration of the alpha-ethyl analog produce the decrease in tissue glutathione levels found after giving methionine sulfoximine or its alpha-methyl analog. The findings strongly indicate that methionine sulfoximine-induced convulsions are closely associated with inhibition of glutamine synthetase rather than with inhibition of gamma-glutamylcysteine synthetase. The alpha-alkyl methionine sulfoximine analogs cannot be catabolized via the corresponding alpha-keto or alpha-imino acids, and, like other alpha-substituted amino acids, are probably not metabolized to a significant extent in vivo; this suggests that the amino acid sulfoximine molecules themselves, rather than their metabolites, are directly involved in the induction of convulsions. Possible explanations for the reported lack of correlation between the occurrence of convulsions and the levels of glutamine synthetase activity (and its substrates and product) are considered. The findings suggest that studies on the mechanism of induction of convulsions may be extended significantly and refined in biochemical terms by the use of other structurally modified convulsant molecules.

Amino Acids↗
PubMed1989

D-1 dopamine agonist administration reduces the threshold for convulsions produced by pilocarpine.

Focal, limbic seizures were produced by systemically administered pilocarpine (200 mg/kg, i.p.); as previously described this dose produces limbic stereotypies but neither convulsions nor seizure-related brain damage. The pretreatment, 5 minutes prior pilocarpine, with the D-1 agonist SKF 38393 (-ED50 = 1 mg/kg; i.p.) induced convulsions similar to those produced by a higher, convulsant dose of pilocarpine. On the other hand, the pretreatment with the D-2 agonist LY 171555 failed to induce convulsions. The D-1 receptor antagonist SCH 23390 prevented the convulsions induced by SKF 38393 plus pilocarpine (200 mg/kg). This study indicates that D-1, but not D-2, receptor stimulation converts subconvulsant doses of pilocarpine into convulsant ones.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Effects of the diterpene sclareol glycol on convulsive seizures.

The effects of the diterpene sclareol glycol (SG) of the labdane family on convulsive seizures induced by pentylenetetrazole (PTZ), picrotoxin and bicuculline in mice were studied. Sclareol glycol potentiated convulsive seizures induced by PTZ (60 and 80 mg/kg) and antagonized the anticonvulsant effect of diazepam. At low doses, SG gave a protective effect against convulsions induced by picrotoxin and bicuculline, and prolonged the latency to convulsions. At larger doses, SG increased the intensity of convulsive seizures. Forskolin, a diterpene of the same family, evoked a protective effect against convulsions induced by bicuculline and prolonged the latency.

Animals↗
PubMed1988

Modulation of gamma-aminobutyric acid-stimulated chloride influx by bicycloorthocarboxylates, bicyclophosphorus esters, polychlorocycloalkanes and other cage convulsants.

gamma-Aminobutyric acid (GABA) stimulated 36Cl- influx into membrane vesicles from rat cerebral cortex at 3 to 300 microM in a concentration-dependent manner with near maximum response at 100 microM. Inhibitory potencies for this GABA (100 microM)-dependent 36Cl- uptake were determined for 16 cage convulsants including 10 bicycloorthocarboxylates and 3 bicyclophosphorus esters and for 8 polychlorocycloalkane insecticides. Inhibition by derivatives of t-butylbicycloorthobenzoate (TBOB) and t-butylbicyclophosphorothionate (TBPS) depended on the substituents at both positions 1 and positions 4. Among them, the 4-cyano-phenyl analog of TBOB was the most potent inhibitor with an IC50 value of 40 nM. Other cage convulsants such as picrotoxinin, tetramethylenedisulfotetramine and p-chlorophenylsilatrane were less potent than TBOB and TBPS. The potencies of bicycloorthocarboxylates, bicyclophosphorus esters and other cage convulsants in inhibiting GABA-stimulated 36Cl- uptake by rat cerebral cortex were significantly correlated with those in inhibiting [35S]TBPS binding to the human and mouse brain receptors (r = 0.96, P less than .01). There also was a significant correlation between the potencies of the polychlorocycloalkanes examined in inhibiting GABA-stimulated 36Cl- uptake and [35S]TBPS binding to the mouse brain receptor (r = 0.94, P less than .01). In these correlations, the polychlorocycloalkanes appear to fall on a different line than that for the bicycloorthocarboxylates, bicyclophosphorus esters and other cage convulsants. Both the cage convulsants and the polychlorocycloalkanes are considered to act at convulsant sites coupled functionally to the GABA receptor chloride ionophore complex and thereby to modulate allosterically or directly the GABA-gated chloride channel leading to their toxic action.

Animals↗
PubMed1995

Chronobiological variations in the convulsive effect of monosodium L-glutamate when administered to adult rats.

Monosodium L-glutamate (MSG) when administered intraperitoneally (i.p.) to rodents induces convulsions and has been used as a model to study various aspects of status epilepticus of multifocal origin. There are circadian variations of susceptibility to convulsions induced by various factors in some animal species. The aim of this work was to learn whether the convulsive effect of MSG in rats would vary when the drug is given at different times of the day. Three subgroups of Wistar rats were given i.p. 5 mg/g MSG at 07:00, 15:00 and 23:00 h, whereas two groups of rats divided into three subgroups of five animals each were used as controls, also being injected at 07:00, 15:00 and 23:00 h. One group was injected with NaCI solution, equimolar to that of MSG (eqNaCI); the other was injected with physiological saline solution (PSS) in proportional volumes to those of the experimental group. Motor behavior was recorded for 4 h following injections in the three groups of animals. Neither signs of brain hyperexcitability, nor convulsions appeared in animals injected with PSS or eqNaCl. With MSG, no variations were seen in the latency period when data from the three subgroups studied were compared among them. Duration of convulsive period when rats were injected at 07:00 h was shorter than that seen at 15:00 and 23:00 h. No significant variations were seen in total number of convulsive episodes in the three subgroups, while the number of seizures per hour and their intensity were significantly greater when animals were injected at 07:00 h than those seen when rats were studied at 15:00 and 23:00 h. Nearly 70% of animals injected at 07:00 h died in status epilepticus, whereas no deaths were recorded in animals injected at 15:00 and 23:00 h. Results could be explained in terms of variations of physiological processes at both the brain and extracerebral tissues involved in MSG metabolism and cerebral excitability, related to circadian rhythms.

Animals↗
PubMed1983

A microwave-hyperthermia model of febrile convulsions.

While convulsions associated with fever represent a serious problem in pediatric medicine, conventional animal models of febrile convulsions suffer numerous technical limitations. A microwave-hyperthermia model that eliminates these problems was tested. Microwave energy was used to increase the core temperature of 13- and 17-day-old rats, resulting in convulsions similar to febrile convulsions in human infants. Rats were irradiated for 10 min in circularly polarized waveguides at 918 MHz, CW (average SAR = 9.4 W/kg at 13 days and 18.0 W/kg at 17 days as determined by twin-well calorimetry). Day 17 irradiated rats were less susceptible to convulsions that were day 13 irradiated rats, indicating an age-dependent decline in susceptibility. Contrary to findings of earlier models using infrared or hot-oven heating, convulsions induced with microwave hyperthermia impaired neither brain growth nor subsequent performance during behavioral testing. Simultaneous measurement of brain and rectal temperatures during microwave irradiation revealed differential heating rates that favor thermal homeostasis in brain tissue.

Animals↗
PubMed1993

Pilocarpine-induced convulsions in rats: evidence for muscarinic receptor-mediated activation of locus coeruleus and norepinephrine release in cholinolytic seizure development.

We recently reported that systemic administration of the anticholinesterase, soman, caused rapid depletion of forebrain norepinephrine (NE) in convulsive but not in nonconvulsive rats. As neurons in nucleus locus coeruleus (LC) provide the bulk of NE innervation to most of the forebrain and the sole source of NE input to the cortex and the olfactory bulb, soman-induced NE depletion was hypothesized to result from activation of LC neurons. This activation was thought to be due to inhibition of acetylcholinesterase by soman, leading to rapid, sustained accumulation of acetylcholine in LC, causing these cells to fire at a high sustained rate. Support for this hypothesis was provided by neurophysiological findings showing that: (i) Systemic administration of soman in anesthetized rats caused a sustained, fivefold increase in the mean firing rate of LC neurons and (ii) microinjections of soman directly into LC caused a similar increase in the firing rate of LC neurons. Soman-induced activation of LC occurred prior to and even in the absence of seizures. As systemic administration of the muscarinic receptor antagonist, scopolamine, rapidly and completely reversed soman-induced activation of LC, it was further hypothesized that activation of LC neurons following soman administration is due to muscarinic receptor stimulation. The rapid release of NE by cholinolytic agents, thus, may play an important role in the initiation and/or maintenance of convulsions. To further test the hypothesis that NE release in soman-intoxicated rats is due to muscarinic activation of LC, we have investigated the effects of the muscarinic receptor agonist, pilocarpine, on NE release and LC discharge. In one set of experiments, rats were injected with a periconvulsive dose of pilocarpine (300 mg/kg, ip); both convulsive and nonconvulsive rats were sacrificed between 1 and 96 h and monoamine levels in the rostral forebrain and olfactory bulb were determined by HPLC with electrochemical detection. NE levels declined substantially only in convulsive rats; forebrain NE levels in convulsive rats rapidly decreased to 50% of control levels at 1 h and to 37% of controls level between 2 and 4 h. The time course and magnitude of these changes were similar to those observed following soman administration in our previous study. Recovery of forebrain NE began at 8 h and was complete by 96 h following pilocarpine administration. Neither dopamine (DA) nor serotonin (5-HT) levels were changed in the forebrain and olfactory bulb of either convulsive or nonconvulsive rats.(ABSTRACT TRUNCATED AT 400 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Effect of bile duct ligation and unilateral nephrectomy on brain concentration and convulsant potential of the quinolone antibacterial agent levofloxacin in rats.

To mimic the excretion route of the quinolone antibacterial agent levofloxacin (LVFX) in humans, we produced an excretion-limited (EL) model in male Sprague-Dawley rats by bile duct ligation and unilateral nephrectomy. We then examined the relationship between brain levels of LVFX and its convulsant effects in control and EL animals. Serum concentrations of LVFX in EL animals (EL + LVFX) were 2.38- and 1.59-fold and brain concentrations were 1.33- and 1.19-fold those of the controls (control + LVFX) at 30 min after a single intravenous injection of 10 and 100 mg/kg LVFX, respectively. Furthermore EL animals became more susceptible to the convulsant effect of LVFX with a 1.28-fold decrease in convulsion-inducing dose. In combination with oral pretreatment with 400 mg/kg 4-biphenylacetic acid (BPAA), convulsion-inducing doses in the control (control + LVFX + BPAA) and EL (EL + LVFX + BPAA) groups were markedly decreased by 2.25 and 9 times that of the control + LVFX group. EL operation and BPAA pretreatment slowed the elimination of LVFX in the serum and brain 4 hr later in the following order: EL + LVFX + BPAA, control + LVFX + BPAA, EL + LVFX, and control + LVFX groups. This order reflects that for the convulsion-inducing doses. These results suggest that EL rats may be a useful model for humans and that the convulsant effect of LVFX with or without BPAA arises not only from the attainment of maximum brain concentration but also from delayed disappearance from the brain.

Administration, Oral↗
PubMed1992

The inhibitory control of the substantia nigra over generalized non-convulsive seizures in the rat.

A system exerting inhibitory control over generalized epilepsies and involving neurons from the substantia nigra has been described by several authors in experimental models of convulsive seizures. In the present study, the existence of such a control system governing absence epilepsy was investigated using models of non-convulsive seizures in the rat. Activation of the GABAergic neurotransmission within the substantia nigra by local injection of GABA agonists (muscimol, THIP) or an inhibitor of GABA degradation (gamma-vinyl GABA) suppresses generalized non convulsive seizures, whether they are genetically determined or induced by systemic injections of gamma-butyrolactone (100 and 200 mg/kg), pentylenetetrazole (20 mg/kg) or THIP (7.5 mg/kg). The ascending dopaminergic nigral output or the GABAergic fibres to the ventromedial thalamus are not critically involved in this control system. By contrast, the GABAergic nigro-collicular pathway appears crucial: bilateral lesion of the superior colliculus abolishes the anti-epileptic effects of intranigral injection of muscimol and blockade of the GABAergic transmission within the superior colliculus results in a suppression of generalized non-convulsive seizures. Finally, activation of collicular cell bodies by low doses of kainic acid significantly suppresses absence seizures. These results suggest the existence of a control system inhibiting generalized non-convulsive seizures which is activated by the release of the tonic inhibition exerted by the nigral GABAergic fibres on collicular neurons. The similarities between this system and the control system described for convulsive seizures are discussed.

Animals↗