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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have used the technique of autoradiography to study the binding of [3H]-GABA to GABAA and GABAB receptors in brains taken from rats that are genetically predisposed to petit mal type seizures. A range of concentrations of [3H]-GABA were employed to test the hypothesis that this predisposition was due to regional changes in either the number of GABAA or GABAB receptors, or affinity of GABA for these receptors. We found no statistical difference in the levels of radioligand binding to GABAA and GABAB receptors in animals susceptible to seizures compared to control animals in any of the brain regions studied over the concentration range 25 nM to 400 nM. This indicated that there was no change in either the Kd (affinity) or Bmax (receptor number) in these animals and that the pharmacological basis for the efficacy of GABAB antagonists in this seizure condition probably lies elsewhere.
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PMID:GABA receptors in rats with spontaneous generalized nonconvulsive epilepsy. 132 80

Gonadal steroid hormones or their derivatives have been shown to modulate the GABA receptor complex and GABA-mediated responses in a manner similar to the benzodiazepines. The present study examines if hormonal status modulates the development of tolerance and/or the neural adaptations in GABAA receptors associated with chronic benzodiazepine exposure. Anticonvulsant effects of diazepam were compared in groups of male, female, orchidectomized, and ovariectomized rats following acute (3 day) and chronic (3 week) exposure to diazepam-filled silastic implants. Results indicated that hormonal status did not significantly modify either the neural levels of drug resulting from the diazepam implants or the diazepam-induced increases in bicuculline seizure thresholds following acute (3 day) exposure. Unlike males and gonad-intact females, ovariectomized rats continued to display elevated seizure threshold values due to the diazepam released from the implants even after chronic diazepam exposure. This suggests that the tolerance to benzodiazepine actions observed in male and intact female rats was prevented by ovariectomy. Analysis of the anticonvulsant effects of additional challenge doses of diazepam in chronic diazepam-treated rats paradoxically suggested that benzodiazepine tolerance developed in all hormone groups. The discrepancies between these two tests of anticonvulsant tolerance may be related to the divergent neural GABAA receptor adaptations seen between hormone groups. Ovariectomized rats displayed a reduction in GABA IC50 values for [3H]bicuculline-thiocyanate binding in cortex following chronic diazepam exposure that was not observed in males or intact females. These results suggest that the diminution of ovarian steroid hormones may modulate the neural GABAergic changes associated with the development of tolerance to benzodiazepine actions during chronic agonist exposure.
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PMID:Effects of gender and gonadectomy on responses to chronic benzodiazepine receptor agonist exposure in rats. 132 64

The aim of this study was to investigate the putative role of GABAB receptors in the development of amygdala kindling in rats. The effects of the GABAB blocker CGP 35348 and the GABAB agonist baclofen on the progressive development of behavioural seizure symptoms (stages 1-5 classified by Racine) and duration of after-discharges (AD) were studied. CGP 35348 at a dose of 300 mg/kg i.p., which blocks central GABAB receptors, moderately but consistently accelerated the development of behavioural seizure symptoms. CGP 35348 had no marked effect on the duration of ADs corresponding to the different seizure stages. L-baclofen (6 mg/kg i.p.) had a dual effect on kindling development. It retarded the development of the behavioural symptoms, but increased the duration of AD. In conclusion, the results suggest that synaptically-released GABA activated GABAB receptors and thereby exerted a depressant effect on kindling development.
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PMID:Blockade of GABAB receptors accelerates amygdala kindling development. 132 69

The binding of 3H-muscimol and 3H-diazepam to rat striatum membranes after picrotoxin- and bicuculline-induced seizures was characterized. No alteration in the maximal binding capacity (Bmax) of 3H-muscimol was observed. However, bicuculline produced a 27% decrease in Kd. Both picrotoxin and bicuculline increased the binding capacity of 3H-diazepam. Bicuculline produced a 86% increase in Kd. These results suggest that the GABA antagonists-induced seizures may modulate 3H-muscimol and 3H-diazepam binding in rat striatum.
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PMID:[Effects of GABA antagonist-induced seizures on 3H-muscimol and 3H-diazepam binding in the rat striatum]. 132 78

1. Strychnine-sensitive glycine receptors are primarily localized in the brainstem and spinal cord where they are the major mediators of postsynaptic inhibition. A compound which acts functionally like a glycine receptor agonist would be potentially useful as a pharmacological tool and as a therapeutic agent for treating disorders of glycinergic transmission. 2. MDL 27,531 (4-methyl-3-methylsulphonyl-5-phenyl-4H-1,2,4-triazole) blocked strychnine-induced tonic extensor seizures in mice following either intraperitoneal (ED50 = 12.8 mg kg-1; 30 min) or oral (ED50 = 7.3 mg kg-1; 30 min) administration. Time course studies revealed a maximal effect at 30-60 min, though significant activity was still seen after 24 h. 3. MDL 27,531 was selective in antagonizing strychnine seizures and little or no activity was seen against seizures produced by other chemical convulsants (bicuculline; quinolinic acid; mercaptopropionic acid); by electrical stimuli (maximal electroshock); or by sensory stimuli (audiogenic seizure susceptible mice). MDL 27,531 blocked pentylenetetrazol-induced seizures with an ED50 = 55 mg kg-1. This profile differed from those of the anticonvulsants diazepam, valproic acid, and diphenylhydantoin. 4. The antagonism of strychnine seizures by MDL 27,531 occurred at doses that did not produce signs of sedation (suppression of spontaneous motor activity), motor ataxia (disruption of rotarod performance), muscle relaxation (inhibition of morphine-induced Straub tail), or CNS depression (potentiation of hexobarbitone sleep time). MDL 27,531 had less side effect potential (as derived from ratios obtained from the above measures) relative to those of the known muscle relaxants diazepam and baclofen. 5. Although MDL 27,531 behaved functionally like a selective agonist at the strychnine-sensitive glycine receptor, the compound did not alter the in vitro binding of [3H]-strychnine to mice brainstem/spinal cord membranes at concentrations of up to 100 microM. In further in vitro binding assays, MDL 27,531 at concentrations of up to 100 microM, did not displace the binding of [3H]-muscimol, [3H]-flunitrazepam, or["S]-t-butylbicyclophosphorthionate to rat cortical membranes. These ligands bind to the 7y-aminobutyric acid (GABA), benzodiazepine, and picrotoxin-convulsant binding sites, respectively.6. MDL 27,531 (10-100mgkg-', i.p.) enhanced binding of the benzodiazepine antagonist [3H]-Ro15-1788 to mouse cerebral cortex in vivo without directly affecting GABA levels.7. Ro 15-1788 (16, 32 mg kg-') significantly blocked the MDL 27,531 antagonism of strychnineinduced seizures, though this antagonism was not competitive. The same doses of Ro 15-1788 produced parallel rightward shifts in the dose-response curves for diazepam inhibition of pentylenetetrazol-induced seizures, consistent with a competitive antagonism.8. Thus, MDL 27,531 acts functionally like an agonist at the strychnine-sensitive glycine receptor in its capacity to reverse selectively strychnine-induced seizures. Though the precise mechanism of action of MDL 27,531 is unknown, MDL 27,531 may act at an allosteric site on the strychnine-sensitive receptor which produces agonist-like activity.
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PMID:MDL 27,531 selectively reverses strychnine-induced seizures in mice. 132 93

In mice, tonic convulsive seizure induced by intravenous administration of caffeine (adenosine A1, A2 receptors antagonist) was significantly potentiated by any one of L-PIA (adenosine A1 receptor agonist), NECA (adenosine A2 receptor agonist) and 2-ClAd (adenosine A1, A2 receptors agonist). The caffeine-induced seizure was unaffected by diazepam (benzodiazepine receptor agonist), but was inhibited by Ro 15-1788 (antagonist or partial agonist). beta-DMCM (antagonist or inverse agonist) increased the seizure. Muscimol (GABA-a receptor agonist), baclofen (GABA-b receptor agonist) and AOAA (GABA transaminase inhibitor) did not show significant effect on caffeine-induced convulsion. Bicuculline (GABA-a receptor antagonist) and picrotoxin (chloride channel blocker) significantly potentiated the convulsion at the doses which did not induce it. Caffeine-induced convulsion was potentiated by NMDA with its non-convulsive dose. CPP (competitive NMDA receptor antagonist) and MK-801 (non-competitive NMDA receptor antagonist) significantly inhibited the seizures. These results suggest that caffeine-induced seizure is not caused by blockade of adenosine receptors. Caffeine may act to beta-carboline sensitive benzodiazepine receptor (Type 1) which has no linkage with GABA-a receptor. Furthermore, it is implied that caffeine plays some role at NMDA receptor calcium ion channel complex.
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PMID:[Effects of agonists and antagonists of benzodiazepine, GABA and NMDA receptors, on caffeine-induced seizures in mice]. 132 1

Female rats have a higher threshold than males for seizures induced by the convulsant pentylenetetrazol, a GABAA receptor-chloride channel complex blocker. No sex difference was observed for the anticonvulsant activities of ethanol or diazepam to protect against pentylenetetrazol seizures. Ovariectomy reduces the pentylenetetrazol seizure threshold of females to that of males. In contrast, females have a lower threshold than males to electroshock seizures. Pentylenetetrazol receptors were compared in males and females and gonadectomized animals by binding of several radioligands to the GABAA receptor complex. No differences were found for these four groups of animals in the binding of [3H]flunitrazepam to the benzodiazepine sites and [35S]t-butyl bicyclophosphorothionate ([35S]TBPS) to the chloride channel/convulsant sites in membrane homogenates, nor for allosteric modulation of binding by GABA, the steroid anesthetic alphaxalone, or the benzodiazepine Ro 5-4864. In tissue section autoradiography, no difference was observed for these same assays nor for the binding of [3H]muscimol in the presence and absence of alphaxalone in several major regions. We conclude that circulating female sex hormones, possibly neurosteroid metabolites of progesterone, known to interact directly with the GABAA receptor complex, are involved in the sex differences in pentylenetetrazol seizure susceptibility.
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PMID:Sex differences in sensitivity to pentylenetetrazol but not in GABAA receptor binding. 133 80

During infusion of branched-chain amino acids (BCAAs) in humans, changes in ventilatory drive, appetite, and sleep have been reported. The mechanism by which BCAAs exert their effects on CNS remains unclear. Picrotoxin is a proconvulsant drug, acting as an antagonist on the GABA-benzodiazepine receptor complex. Twenty rats were randomized to receive either an IP injection with 4% BCAAs (300 mg/kg; 8 ml/kg) (n = 10) or placebo (saline 8 ml/kg) (n = 10). The mean latency time from injection to onset of seizures was recorded as an indication of the seizure threshold. Latency time was significantly longer for BCAAs than for placebo, 11.2 (+/- 1.9) vs. 8.3 (+/- 1.8) min. Thus, a BCAA injection increased the seizure threshold to picrotoxin (p < 0.03). This suggests that BCAA infusion may exert effects on the GABA-benzodiazepine receptor complex.
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PMID:Branched-chain amino acids increase the seizure threshold to picrotoxin in rats. 133 82

Anticonvulsant properties of compounds that enhance GABA-mediated inhibition through modulatory sites on the GABAA receptor [phenobarbital (PB), clonazepam (CZP), alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone (alpha-EMTBL)] were compared with anticonvulsant effects of compounds believed to be antagonists at these modulatory sites (Ro15-1788 and alpha-isopropyl-alpha-methyl-gamma-butyrolactone gamma-IMGBL)] and to 4,5,6,7-tetrahydroisoxazolo-[4,5-c]-pyridin-3-ol (THIP, GABAA receptor agonist), (+/-) baclofen (GABAB receptor agonist), and gamma-vinyl GABA, a compound that increases endogenous GABA. The compounds were tested for their ability to block experimental seizures caused by maximal electroshock, pentylenetetrazol, picrotoxin, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), bicuculline (BIC), aminophylline, strychnine, and t-butyl-bicyclophosphorothionate (TBPS) in mice. CZP blocked all but strychnine seizures. PB was also highly effective, blocking all but TBPS seizures. alpha-EMTBL, representing a new class of experimental anticonvulsant drugs, prevented all seizures except strychnine (STR)- and aminophylline-induced seizures. The antagonists are effective only against one convulsant stimulus. Ro15-1788 and alpha-IMGBL prevented only DMCM- and pentylenetetrazol (PTZ)-induced seizures, respectively. THIP and gamma-vinyl GABA both blocked only BIC and picrotoxin seizures. Baclofen had no anticonvulsant activity. These data demonstrate that compounds that increase neuronal inhibition by potentiating the action of GABA have a broader spectrum of anticonvulsant action than either antagonists or GABAmimetic agents or compounds that increase endogenous GABA.
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PMID:Relative anticonvulsant effects of GABAmimetic and GABA modulatory agents. 133 54

The direct or indirect interference with GABA-mediated neurotransmission results in convulsive seizure activity in humans and experimental animals. When this convulsant effect is experimentally analyzed, it turns out to be a product of discrete and restricted cerebral sites of drug action. Depending upon the brain circuitry affected, different convulsant patterns are produced. Acute interference with GABA transmission in convulsant trigger sites in the forebrain evokes convulsant seizures which can be clearly distinguished from those evoked by interference with GABA transmission in the hindbrain convulsant sites. While acute alterations of forebrain seizure susceptibility do not change hindbrain seizure susceptibility, chronic or repeated exposure to seizures may cause simultaneous "kindling" of both systems. In addition to the specific convulsant sites of action of GABA antagonists in the brain there are specific sites where GABA antagonists exert an anticonvulsant action. The ability of a chemical agent to evoke a convulsive seizure by interfering with GABA transmission depends upon the relative effect of the agent on GABA transmission in different brain areas as well as its effect on other excitatory and inhibitory neurotransmitters with which GABA interacts.
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PMID:Role of GABA in the genesis of chemoconvulsant seizures. 133 80


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