Evaluation of different beta-carbolines in Mongolian gerbils with reflex epilepsy.

Three benzodiazepine (BZ) receptor ligands of the beta-carboline group, namely the BZ receptor agonist ZK 93 423, the partial agonist ZK 91 296, and the antagonist ZK 93 426, were studied in epilepsy-prone Mongolian gerbils with different seizure types. Diazepam and clonazepam were included in these studies for comparison. In vivo binding studies in gerbils showed that all compounds were potent in displacing [3H]lormetazepam from binding sites in cerebellum and forebrain. Except for ZK 93 426, all drugs proved capable of dose dependently protecting gerbils from minor (myoclonic) and major (tonic-clonic) seizures induced by air blast stimulation. For ZK 93 423, ZK 91 296, diazepam and clonazepam, a highly significant correlation was found between anticonvulsant ED50S and ED50S for displacement of [3H]lormetazepam binding. Calculation of receptor occupancy revealed that beta-carbolines and benzodiazepines displayed anticonvulsant effects in gerbils at low occupancy (8-15% in forebrain). Even at almost total receptor occupancy, the BZ receptor antagonist ZK 93 426 was without any effect on seizure behaviour but antagonized the anticonvulsant effect of ZK 91 296. In contrast to diazepam, ZK 91 296 was devoid of any sedative side-effects even at 90% receptor occupancy. The data suggest that anticonvulsant beta-carbolines deserve interest as a new type of anticonvulsant drug.

Agonist--antagonist interaction on dopamine receptors in brain, as reflected in the rates of tyrosine and tryptophan hydroxylation.

The effect of haloperidol and apomorphine, and both drugs in combination, on the first steps in the synthesis of catecholamines and 5-hydroxytryptamine (5-HT) has been studied in three rat brain regions. The rate of formation of dopa and 5-hydroxytryptophan (5-HTP) was studied by measuring the accumulation of these amino acids during 30 min after administration of the inhibitor of the aromatic L-amino acid decarboxylase, NSD 1015 (3-hydroxybenzylhydrazine HCl). Haloperidol caused an increase in dopa and no change in 5-HTP formation. The threshold dose was severalfold higher in the noradrenaline-predominated hemisphere portion than in the dopamine-rich striatal and limbic regions, suggesting a higher affinity of haloperidol for dopamine than for noradrenaline receptors. Apomorphine caused a decrease in dopa formation in all three brain regions studied, although the effect was much more pronounced in the regions dominated by dopamine. The threshold dose was about 30 microng/kg, i.e. an order of magnitude lower than the threshold dose for apparent postsynaptic dopaminergic receptor activation. This discrepancy is suggested to be due to preferential activation of inhibitory dopaminergic autoreceptors by low apomorphine doses. This phenomenon may also contribute to explain the complex dose-response curves of apomorphine. Low doses of apomorphine caused a decrease and high doses an increase in 5-HTP formation. These effects, like those on noradrenaline synthesis, are suggested to be secondary to activation of dopaminergic pre- and post-synaptic receptors. The interaction between apomorphine and haloperidol with respect to dopa formation appears to be largely explicable on the assumption of a competition between an agonist and an antagonist for dopaminergic receptors. However, very large doses of apomorphine cause a haloperidol-resistant inhibition of tyrosine, and probably also tryptophan, hydroxylation, which may be due to a direct inhibition of the aromatic amino acid hydroxylase involved.