Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Central type benzodiazepine receptors were studied in vivo by positron emission tomography in brain areas of 2 different groups of the baboon Papio papio: non-photosensitive (group 1) and those with an allylglycine-induced decrease in GABA-mediated inhibition (group 2). Further, a naturally photosensitive Papio papio (+3 level of photosensitive response) was compared to both groups. Regional brain binding of the specific benzodiazepine receptor ligand, [11C]Ro 15-1788, was not significantly different between groups 1 and 2. In addition, the data from the naturally photosensitive Papio papio did not seem to differ markedly from groups 1 and 2 either. Pharmacological effects of increasing doses of beta-CCM (0.05-3 mg/kg i.v.) and regional benzodiazepine receptor occupancy by the drug were simultaneously studied using electroencephalographic activity recording and positron emission tomography. A positive correlation was observed between the degree of photosensitivity of the baboon and sensitivity to the action of beta-CCM, with increasing convulsant efficacy of beta-CCM in going from group 1 to the naturally photosensitive baboon, then to group 2. Dose-related displacement curves of [11C]Ro 15-1788 binding by beta-CCM revealed that reduction in brain GABA concentration did not modify the inhibitory potency of beta-CCM on [11C]Ro 15-1788 binding in cerebral cortex. This suggests a lack of detectable in vivo allosteric effects of GABA on beta-CCM binding during beta-CCM-induced seizures. Thus, a given dose of beta-CCM displayed increasing pharmacological potency in going from baboons with the lowest photosensitivity to those with the highest, whereas benzodiazepine receptor occupancy by beta-CCM was similar in the cerebral cortex of the different baboons. Conversely, a given level of convulsant activity of beta-CCM was related to a different benzodiazepine receptor occupancy by the drug, depending on the photosensitivity of Papio papio. A given dose of a drug may, thus, have a different pharmacological potency when occupying the same number of receptors, depending on the physiopathological state of the subject.
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PMID:Relationships between benzodiazepine receptors, impairment of GABAergic transmission and convulsant activity of beta-CCM: a PET study in the baboon Papio papio. 164 49

1. The pharmacological properties of the benzodiazepine receptor ligand, FG 8205 (7-chloro-5,6-dihydro-5-methyl-6-oxo-3-(5-isopropyl-1,2,4-oxadiazol++ +-3-yl)-4H- imidazol[1,5a][1,4]benzodiazepine) have been examined. 2. FG 8205 potently displaced [3H]-flumazenil binding in rat cortical membranes with a Ki of 3.3 nM, but was inactive at 13 neurotransmitter recognition sites. 3. Consistent with a partial agonist profile, the affinity of FG 8205 for the benzodiazepine recognition site was increased in the presence of gamma-aminobutyric acid (GABA, 300 microM) by a degree (-log [IC50 in the presence of GABA/IC50 alone] = 0.34) significantly less than found for diazepam (0.46). FG 8205 also potentiated the inhibitory potency of the GABAA-receptor agonist, isoguvacine, on the hippocampal CA1 population spike and, again, the maximum shift (-log dose-ratio = 0.2) was significantly less than that seen with diazepam (0.4). 4. In anticonvulsant studies, the ED50 doses of FG 8205 and diazepam needed to antagonize seizures induced by pentylenetetrazol (PTZ) or by sound in audiogenic seizure prone mice were similar with values of 0.2-0.3 mg kg-1, i.p. However, even high doses of FG 8205 (50 mg kg-1) did not protect against seizures induced by electroshock. 5. FG 8205 released responding suppressed by footshock in a rat operant conditioned emotional response task over the dose range 0.5-50 mg kg-1 (i.p.). Similar doses of FG 8205 had a marked taming effect in cynomolgus monkeys. However, measures of sedation and ataxia (as measured by rotarod in the mouse, climbing behaviour in the rat, and by scoring arousal and co-ordination in primates) were slight and only transiently affected by FG 8205, and FG 8205 significantly antagonized the rotarod performance deficit induced by diazepam in the mouse. 6. While the potentiation by FG 8205 of the response to isoguvacine in the rat hippocampal slice and the anxiolytic-like effects of the compound in both rats and primates were reversed by the benzodiazepine receptor antagonist, flumazenil, high doses of the antagonist were able only marginally to block the protective effects of FG 8205 against seizures induced by PTZ in the mouse. 7. Thus, FG 8205 does not show the marked motor impairment characteristic of full agonists at the benzodiazepine receptor, consistent with its partial agonist profile in in vitro assay systems. Nevertheless, the compound has sufficient intrinsic activity to maintain high efficacy in anticonvulsant and anxiolytic tests.
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PMID:The pharmacological properties of the imidazobenzodiazepine, FG 8205, a novel partial agonist at the benzodiazepine receptor. 196 8

The intrinsic effects of the benzodiazepine receptor ligand beta-CMC (3-(methoxycarbonyl)-amino-beta-carboline) and its interaction with the anticonvulsant and sedative effects of diazepam were assessed. beta-CMC (100 mg/kg i.p.) significantly elevated seizure threshold to bicuculline. beta-CMC (10 mg/kg) failed to alter the anticonvulsant action of diazepam (5 mg/kg i.p.), but significantly attenuated diazepam's sedative effect. A higher dose of beta-CMC (40 mg/kg) did attenuate diazepam's anticonvulsant action. The data suggest that beta-CMC is a partial agonist at benzodiazepine receptors.
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PMID:3-(Methoxycarbonyl)-amino-beta-carboline reduces both the sedative and anticonvulsant effects of diazepam. 276 29

Repeated administration of the beta-carboline benzodiazepine receptor ligand FG 7142 produces sensitization to its effects so that full seizures develop (chemical kindling); initially it is only pro-convulsant. The present study investigated alterations in the function of drugs which act at the different sites at the gamma-aminobutyric acid (GABA) benzodiazepine receptor complex, after repeated administration of FG 7142. In FG 7142 kindled mice decreased anticonvulsant and hypothermic effects of the GABA agonist muscimol were observed. The hypothermic effects of the GABA agonist progabide were reduced. In contrast a small increase in the hypothermic effect of pentobarbitone was seen. The convulsant effects of bicuculline and picrotoxin were unaltered when they were given intravenously but marginally increased when they were given by the intraperitoneal route. No changes were seen in the hypothermic effects of these drugs. No significant changes were seen in the convulsant or hypothermic effects of pentylenetetrazol. These results suggest that kindling with FG 7142 may alter GABA receptor function.
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PMID:The effects of drugs acting at the GABAA-receptor/ionophore after chemical kindling with the benzodiazepine receptor ligand FG 7142. 301 86

The effects of the beta-carboline benzodiazepine receptor ligand FG 7142 upon local cerebral glucose utilization have been examined in conscious rats using the quantitative [14C]2-deoxyglucose autoradiographic technique. FG 7142 (1-10 mg/kg i.v.) produced behavioural changes consistent with an anxiogenic action. At the largest dose of FG 7142 (10 mg/kg) 30% of the animals experienced overt convulsions. In the data analysis animals were divided according to the behavioural response elicited by the drug. In animals not expressing convulsions, FG 7142 (1-10 mg/kg) effected increases in glucose utilization in 33 of the 65 regions examined. The majority of changes were confined to limbic structures with pronounced effects occurring in the mammillary body, anterior thalamic nuclei, septal nuclei and the oriens and molecular layers of the hippocampus. Glucose use in other structures associated with auditory and visual processing, such as the medial and lateral geniculate body, and associated cortical areas, was also significantly increased. However, brain regions involved in motor control were minimally affected. The patterns of local cerebral glucose use in animals expressing FG 7142-induced convulsions were contrasted with those from an equivalent non-seizure group. Some limbic structures which were significantly affected by FG 7142 (non-seizure group) displayed a further increase in glucose utilization during convulsions. These included the mammillary body and septum. Many other limbic structures (anterior thalamic nuclei, CA fields of the hippocampus and basolateral amygdala) did not display this further rise in glucose utilization. In the cortical amygdala, lateral preoptic area of the hypothalamus, nucleus accumbens and lateral elevations in glucose utilization were restricted to those animals experiencing overt convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effects of FG 7142 upon local cerebral glucose utilization suggest overlap between limbic structures important in anxiety and convulsions. 321 32

A method for measuring seizure thresholds using an intravenous infusion of a convulsant beta-carboline benzodiazepine receptor ligand (DMCM) is reported. Seizure thresholds to DMCM are elevated by the benzodiazepine receptor agonist, flurazepam and antagonist, Ro 15-1788, and the proconvulsant beta-carboline, FG 7142. Various other anticonvulsant also antagonise DMCM seizures. Selectivity for the benzodiazepine/GABA receptor complex is demonstrated since bicuculline and pentylenetetrazol lowered thresholds whereas strychnine and N-methyl DL-aspartate did not.
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PMID:Investigating benzodiazepine receptor function in vivo using an intravenous infusion of DMCM. 609 8

Benzodiazepine receptors were investigated in the cerebral cortex, the hippocampus, the brainstem, and the cerebellum of audiogenic seizure (AGS)-susceptible and seizure-resistant (ER) control rats. In AGS-susceptible rats of Sprague-Dawley descent, muscimol (10-6 M and 3 x 10-5 M) activated the binding of 3H-diazepam (0.4 nM) significantly less than in ER-rats. This finding may be strain selective, since it was not observed in AGS-susceptible rats of Wistar descent. Specific binding of the convulsant benzodiazepine receptor ligand methyl 6,7-dimethoxy-4-ethyl carboline-3-carboxylate (3H-DMCM), the benzodiazepine receptor ligand 3H-diazepam and the chloride channel directed cage convulsant t-butylbicyclophosphorothionate 35S-TBPS were not significantly changed in AGS-susceptible as compared to control rats. Our findings indicate that a disturbance at the level of the benzodiazepine receptor/GABA receptor/chloride channel complex is not a likely general aetiological factor for audigenic seizures in rats.
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PMID:A study on benzodiazepine receptor binding in audiogenic seizure-susceptible rats. 609 92

The effects of the acute and chronic administration of the beta-carboline benzodiazepine receptor ligand, FG 7142 were studied in mice. On acute administration FG 7142 (at doses between 10 and 40 mg kg-1) lowered seizure thresholds to infused pentylenetetrazol (PTZ) but showed an unusual dose-response curve in that higher doses had less effect. The duration of action was considerably longer than that of other beta-carbolines, such as ethyl-beta-carboline-3-carboxylate (beta CCE). During repeated administration, doses of FG 7142 which were initially proconvulsant subsequently produced generalized seizures on average in 60% of animals after 12 once daily treatments. This seemed to be a form of chemical kindling. The effects of different drug administration regimes were studied. Once daily dosage was shown to be the optimum for kindling production, and was therefore used for subsequent experiments. Kindling lasted for at least one month after 12 single once daily doses of 40 mg kg-1 (FG 7142). The administration of the benzodiazepine antagonist Ro 15-1788 concurrent with FG 7142 prevented kindling. When Ro 15-1788 was given to kindled animals along with a challenge dose of FG 7142, it prevented the expression of kindled seizures. These data show that kindling is mediated via the benzodiazepine receptor.
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PMID:Acute and chronic effects of the benzodiazepine receptor ligand FG 7142: proconvulsant properties and kindling. 609 29

The gamma 2 subunit of the gamma-aminobutyric acid type-A (GABAA) receptor is associated with the actions of benzodiazepines and related drugs. A phosphorothioate-modified antisense oligodeoxynucleotide directed against the gamma 2 subunit was given by i.c.v. injection (18 micrograms in 2 microliters saline) to male Sprague-Dawley rats every 12 h for 3 days. Controls received the corresponding sense oligodeoxynucleotide. 4-6 h after the last i.c.v. treatment, rats were given methyl-beta-carboline-3-carboxylate (beta-CCM), a benzodiazepine "inverse agonist', by slow i.v. infusion. Compared to naive rats, the beta-CCM threshold dose was not affected by the sense oligodeoxynucleotide, but was increased 87% in antisense oligodeoxynucleotide-treated rats. The treatment had no effect on the seizure threshold for picrotoxin. Both antisense and sense oligodeoxynucleotide treatments slightly increased the threshold for strychnine seizures. The results suggest that antisense oligodeoxynucleotide treatment altered GABAA receptor composition and interfered with the actions of a benzodiazepine receptor ligand in vivo, and may provide a tool for studying regulation of receptor structure and function.
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PMID:Treatment with an antisense oligodeoxynucleotide to the GABAA receptor gamma 2 subunit increases convulsive threshold for beta-CCM, a benzodiazepine "inverse agonist', in rats. 881 15