Differentiation of drug-induced rhythmical activities in the rabbit's brain by a benzodiazepine antagonist.

The effect of a benzodiazepine antagonist, ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5a] [1,4]benzodiazepine-3-carboxylate (Ro 15-1788), on the cerebello-rubral rhythm induced by a water soluble benzodiazepine derivative (medazepam hydrochloride) or by a barbiturate (pentobarbital sodium) was investigated in the rabbit. The frequency of this rhythm which depends on the depth of the central depression caused by either of these agents was used for the drug interaction study. Ro 15-1788 when given alone up to 10 mg/kg did not cause any changes in the cerebello-rubral and the neocortical electrical activities. Ro 15-1788 (0.5 and 2.0 mg/kg) was effective in antagonizing the medazepam-induced cerebello-rubral rhythm and the rhythmic discharges of Purkinje cells in a dose-dependent manner. The antagonistic effect was also observed in the electrocorticogram. The pentobarbital-induced cerebello-rubral rhythm and the neocortical activity were not influenced by Ro 15-1788 up to 5 mg/kg. Thus, the similar effect of barbiturates and benzodiazepine derivatives on the cerebello-rubral system seems to be mediated by different pharmacodynamic actions. The findings are in line with previous studies indicating a selective antagonism of Ro 15-1788 and benzodiazepine derivatives.

Drug-induced rhythmic burst activity of cerebellar neurons.

The discharge of cerebellar neurons was investigated in the rabbit and the rat under the influence of pentobarbital, diazepam or medazepam. In the rabbit, these drugs are known to induce a rhythm ranging between 4 and 25 Hz in the red nucleus (RN) and the cerebellum (Cb). Purkinje cells (P cells) in the intermediate zone of the cerebellar cortex as well as neurons of the interposed nucleus (IPN) were found to discharge with burst patterns fully synchronized with the drug-induced RN rhythm. In contrast, P cells in the medial cerebellar zone responded to these drugs only with changes in their discharge rate. Since P cells of the intermediate longitudinal zone project to the RN mainly via the IPN, the present findings complement our previous results, indicating that the rhythmic electrical activity in the RN is initiated by the cerebellum. The three drugs had similar effects on the activity of cerebellar units in the rabbit and the rat. The investigation also shows that, in spite of the uniform morphological structure of the cerebellar cortex, P cells do not respond uniformly to a given drug: the diversity of findings published on the P cell response to barbiturates or benzodiazepine derivatives may be explained by differences in the recording sites.

[Electroencephalographic Investigations of 4-Aminopyridine (author's transl)]. / Elektroenzephalographische Untersuchungen von 4-Aminopyridin.

Electroencephalographic investigations of 4-aminopyridine were carried out in the non-anesthetized, immobilized rat. Under the influence of this agent seizure-like activity appeared in the hippocampal and subsequently in the neocortical recordings. This effect was antagonized by pretreatment with diazepam. The discussion deals with the central cholinergic action of 4-aminopyridine.

[Description of the electrocerebellogram by Parcor-coefficients (author's transl)]. / Beschreibung des Elektrozerebellogramms mittels Parkor-Koeffizienten.

The electrocerebellogram of the rabbit was analysed by the Parcor-coefficients. The results show that this bioelectrical activity may be described by two Parcor-coefficients. No changes in these coefficients were found under the influence of physostigmine or scopolamine. Differences between the rhythms induced by pentobarbital, harmaline and strychnine were established.

Effect of harmaline on the cerebello-rubral system.

Harmaline induces synchronous rhythms in both the cerebellum and the red nucleus of the rabbit. The level of synchronization is lower in the red nucleus than in the cerebellar cortex, probably because the cerebello-rubral pathway and the red nucleus neurons only participate poorly in the harmaline-induced olivo-cerebellar rhythm.

[Effect of combined application of halothane and some central depressants (author's transl)]. / Beeinflussung der Halothannarkose durch zentral dämpfend Pharmaka

The combined effects of halothane and various central depressants were studied in mice by means of an isobolographic method which allows the statistical evaluation of interactions. A loss of the righting reflex for at least 2 min was taken as the criterion for the synchronisation of the peak time of drug effects. All interactions turned out to be supra-additive, more pronounced in the case of diazepam and flunitrazepam than in the case of medazepam, pentobarbitone or ethanol. The organic solvent used for the solution of diazepam and flunitrazepam was found to contribute to the observed interactions. The difficulties of estimating and classifying combined drug effects as well as their clinical relevance are discussed.

Neurotoxicity and CSF level of three penicillins.

The electrocortical activity and the antibiotic concentration in serum and CSF were investigated in rabbits after i.v. administration of benzylpenicillin, ampicillin and oxacillin. In contrast to ampicillin and oxacillin, benzylpenicillin induced a pronounced epileptogenic activity. The different epileptogenic activity of the three penicillins cannot be explained by the difference in the CSF level of these agents only. The intensity of the epileptogenic activity and the CSF level after benzylpenicillin administration were markedly influenced by the experimental procedure in that curarized animals exhibited both higher CSF levels and more intense seizure activities than non-curarized animals. Factors are discussed which may be responsible for the different neurotoxic potency of the three penicillins and for the dependence of the benzylpenicillin-induced seizure intensity on the experimental procedure.

Rhythmic cerebellar and cortical electric activity in tetanus intoxicated rabbits.

Intravenously injected tetanus toxin induced general tetanus within 12 to 37 h. The EEG of precentral, parietal, and occipital areas of the cerebellum revealed a highly rhythmic activity. In local tetanus of the limbs or in brainstem tetanus this rhythm could not be registered.

Action of six commonly used benzodiazepines on isolated guinea-pig ileum preparation.

The spasmolytic activity of six commonly used benzodiazepines was investigated on isolated guinea-pig ileum preparation. All six substances proved to be non-competitive antagonists of carbachol and barium chloride, the pD'2 values ranging between 3.23 and 4.37 in the presence of either agonist. The significance of these findings is discussed.

[Action of central depressants on the nitrous oxide anesthesia (author's transl)]. / Wirkung zentral dämpfender Pharmaka auf die Stickoxydul-Narkose

The synergistic action of seven central depressants three benzodiazepines, two neuroleptics on barbiturate and morphine on the anesthetic activity of nitrous oxide was studied in mice. The benzodiazipines and among them nitrazepam and flunitrazepam were found to be the most potent drugs in this respect; morphine on the other hand was innefective even in toxic doses. There was a significant difference in the slope of log dose-response curves; these curves were much steeper for pentobarbitone, droperidol and chlorpromazine than for nitrazepam, flunitrazepam, and diazepam. The theoretical and practical implications of this difference are discussed.