1-methyl-beta-carboline-3-carboxylic-acid and Seizures

The convulsive effects of methyl beta-carboline-3-carboxylate (beta-CCM), a benzodiazepine receptor ligand, are different in two inbred strains of mice: BALB/cBy mice are more sensitive to beta-CCM than C57BL/6J mice. In the present article, we report the effects of [3H]flunitrazepam binding in these two strains, which suggest a possible explanation of the differences in their sensitivity to beta-CCM by the involvement of brain benzodiazepine receptors.

Topics: Animals; Brain; Carbolines; Clonazepam; Convulsants; Flunitrazepam; Kinetics; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Receptors, GABA-A; Seizures; Species Specificity; Strychnine

The spontaneous activity of neurons in the pars reticulata of substantia nigra (SNpr) was studied in chloral hydrate anesthetized rats. As a function of dose, intravenous diazepam decreased, and methyl-beta-carboline-3-carboxylate (beta CCM) increased discharge frequency. Two days after terminating a one week treatment with flurazepam (FZP), both diazepam and beta CCM showed decreased ability to alter SNpr neuronal activity. Neither residual FZP nor down-regulation of benzodiazepine receptors can account for these results. In contrast, behavioral testing revealed no change in the ability of i.v. beta CCM to cause convulsions, suggesting that sites other than the SNpr are of prime importance in expressing the convulsant actions of systemically injected beta CCM.

Topics: Animals; Benzodiazepines; Carbolines; Chloral Hydrate; Diazepam; Drug Tolerance; Electrophysiology; Male; Neurons; Rats; Rats, Inbred Strains; Seizures; Substantia Nigra

The inbred mouse strains BALB/cBy (C) and C57BL/6By (B6) differed significantly in their susceptibility to seizures induced by the benzodiazepine inverse agonist methyl beta-carboline-3-carboxylate (beta-CCM). Following a 5 mg/kg injection of beta-CCM, 74% of C (n = 35) and 13% of B6 (n = 40) mice exhibited a convulsion. No sex difference was found. Analysis of the reciprocal F1s failed to show either maternal environmental and/or heterosomal effects. A genetic analysis of the strain difference in susceptibility to beta-CCM-induced seizures using recombinant inbred strains (RIS) was performed. The strain distribution for the RIS showed a two group partition. Statistical analysis showed that, although a one-segregating-unit model could not be rejected to explain the strain difference in beta-CCM-induced seizures, some of the evidence weakened the one-segregating-unit hypothesis.

Topics: Animals; Carbolines; Convulsants; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred Strains; Receptors, GABA-A; Seizures; Sex Factors; Species Specificity

Certain pharmacological properties of methyl beta-carboline-3-carboxylate (beta-CCM), a benzodiazepine receptor ligand, have been investigated in chicks. Although beta-CCM has been established previously as an "inverse agonist" of benzodiazepine receptors in rodents, having effects opposite to those of benzodiazepines in a variety of tests, in chicks this compound had a different pharmacological profile. Firstly, in contrast to the overt convulsant action of beta-CCM in other species, beta-CCM (0.05-40 mg/kg) did not produce convulsions by itself in chicks, but it was only proconvulsant. Secondly and most surprisingly, beta-CCM, like diazepam, produced in chicks a sedation which could be blocked by the benzodiazepine receptor antagonist Ro 15-1788. Thus it appears that beta-CCM can function both as an agonist and as an inverse agonist in this animal.

Topics: Animals; Benzodiazepinones; Carbolines; Chickens; Convulsants; Flumazenil; Hypnotics and Sedatives; Receptors, GABA-A; Seizures

The electroencephalographic (EEG) effects of inverse benzodiazepine (BDZ) agonists have been studied in rabbits after i.v. administration. A dose-dependent progression of three different stages of EEG changes have been observed with inverse BDZ agonists. At first, trains of slow waves in the occipital cortex occur, followed by trains of spike-and-wave complexes in the sensorimotor cortex. These two stages are superimposed on a desynchronized cortical activity, accompanied by an enhancement of the hippocampal theta rhythm. These EEG changes parallel a state of alertness. The third stage is characterized by generalized grand-mal seizures made up of high voltage spikes in the cortical and subcortical brain areas accompanied by generalized tonico-clonic convulsions. No modification of electrical activity is observed at the level of the spinal cord. Methyl-beta-carboline-3-carboxylate (beta-CCM) (at doses higher than 0.2 mg/kg) and 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (at doses higher than 0.4 mg/kg) elicit all three stages, whereas ethyl-beta-carboline-3-carboxylate (beta-CCE) (0.2-2 mg/kg) and N-methyl-beta-carboline-3-carboxamide (2-20 mg/kg) only elicit the first two, and finally CGS 8216 only the first. The extent of the EEG progression by inverse BDZ agonists may therefore be used as an index of the efficacy of each compound. The BDZ antagonists Ro 15-1788 and Ro 15-3505 (0.3 mg/kg or higher), which do not change the EEG pattern, block the effects of the convulsant and subconvulsant doses of the inverse BDZ agonists, giving rise to a desynchronized EEG pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzodiazepinones; Carbolines; Diazepam; Electroencephalography; Flumazenil; Male; Pyrazoles; Rabbits; Receptors, GABA-A; Seizures

The convulsant properties of methyl beta-carboline-3-carboxylate (beta-CCM), which is a homologue of a putative benzodiazepine receptor ligand in the mammalian central nervous system, were examined in cats. Subcutaneous injection of 0.5 mg/kg of the beta-CCM produced various degrees of myoclonic jerks always accompanied by cortical spike burst. Some autonomic symptoms such as tachypnea, hypersecretion of thick mucous saliva, vomiting and mydriasis were also presented. Subcutaneous injection of 1.0 mg/kg of the compound induced a generalized tonic-clonic convulsion. Injection of the same amount of the drug 1 hour later in the same cats failed to provoke a generalized seizure. Repeated injection of the same dose 3 hours later provoked a generalized seizure, but with a longer latency. However, repetition of the experiments 24 hours after or 10 days after the first injection consistently induced the same type of generalized seizure with the same latency as the first injections. These results support the suggestion that the pharmacological effect, especially the convulsive effect, of beta-CCM is dose-related, reversible and reproducible in the same cats and among different cats. Moreover, the postictal refractory period in this model of epilepsy may continue about for 3 hours.

Topics: Animals; Benzodiazepines; Carbolines; Cats; Cerebral Cortex; Dose-Response Relationship, Drug; Electroencephalography; Electromyography; Indoles; Seizures

Injected i.v. into baboons, Ro 15-1788 (a benzodiazepine antagonist) and propyl-beta-carboline-3-carboxylate did not modify either the behavior or the electroencephalogram at doses up to 2 mg/kg. Methyl-beta-carboline-3-carboxylate is a potent convulsant at doses of 20 micrograms/kg in photosensitive baboons and 100 micrograms/kg in non-photosensitive baboons. These convulsive doses of methyl-beta-carboline-3-carboxylate are effectively antagonized by 0.5 mg/kg of Ro 15-1788 and also by 2 mg/kg of propyl-beta-carboline-3-carboxylate.

Topics: Animals; Benzodiazepinones; Carbolines; Diazepam; Flumazenil; Indoles; Papio; Photosensitivity Disorders; Seizures; Time Factors

The effects of the methyl, ethyl and propyl esters of beta-carboline-3-carboxylic acid have been studied in vitro and in vivo. All three esters were found to be potent inhibitors of 3H-flunitrazepam binding in the rat cerebellum and cerebral cortex in vitro. In vivo, the methyl and ethyl esters were potent proconvulsant agents, whereas the propyl ester was not. Furthermore, the methyl ester produced convulsions which were blocked by the ethyl and propyl esters as well as by diazepam. These in vivo differences may be due to the beta-carboline esters having different proportions of agonistic and antagonistic actions at their recognition sites.

Topics: Animals; Carbolines; Cerebellum; Cerebral Cortex; Electroshock; Indoles; Male; Muridae; Seizures