Enhancement of gamma-aminobutyric acid binding by the anxiolytic beta-carbolines ZK 93423 and ZK 91296.

The effects of two anxiolytic beta-carboline derivatives, ZK 93423 and ZK 91296, on the binding of gamma-[3H]aminobutyric acid ([3H]GABA) to brain membrane preparations from rat cerebral cortex were examined. ZK 93423 concentration-dependently enhanced the specific binding of [3H]GABA, with a maximal increase of 45% above control at a 50 microM concentration. A less pronounced increase was induced by diazepam and by the partial agonist ZK 91296. Scatchard plot analysis revealed that the effect of ZK 93423 was due to an increase in the total number of high- and low-affinity GABA binding sites. The action of ZK 93423 was mediated by benzodiazepine recognition sites since it was blocked by the benzodiazepine antagonists Ro 15-1788 and ZK 93426 at concentrations that failed to modify [3H]GABA binding on their own. Moreover the stimulatory effect of ZK 93423 on [3H]GABA binding was also blocked by the beta-carboline inverse agonist ethyl beta-carboline-3-carboxylate. These results are consistent with the view that ZK 93423 and ZK 91296, similarly to benzodiazepines, exert their pharmacological effects by enhancing the GABAergic transmission at the level of the GABA/benzodiazepine receptor complex.

Effect of (-)-cathinone, a khat leaf constituent, on dopaminergic firing and dopamine metabolism in the rat brain.

The effect of (-)-cathinone (CAT), an alkaloid from khat leaves, on brain dopamine (DA) metabolism and on the firing rate of nigral DA neurons was studied in rats, in comparison with that of d-amphetamine. Like d-amphetamine, CAT (8-40 mg/kg i.p.) decreased DOPAC levels in the caudate nucleus, nucleus accumbens and frontal cortex, without modifying DA concentrations. CAT showed approximately one fifth of the potency of d-amphetamine in this effect. CAT, injected i.v. to unanesthetized, paralyzed rats, inhibited the firing rate of DA neurons in the substantia nigra, pars compacta, showing a similar potency to that of d-amphetamine in this respect. CAT-induced inhibition of dopaminergic firing was reversed by haloperidol.

Sleep induced by low doses of apomorphine in rats.

The effect of apomorphine on the EEG of freely moving rats was studied. Apomorphine at the dose of 1 mg/kg caused stereotypy and a marked reduction of total sleep. On the contrary, acute subcutaneous administration of apomorphine at the dose of 100 microgram/kg, or less, markedly increased the amount of total sleep (corresponding mostly to synchronized sleep). Moreover, the infusion of apomorphine (80 microgram/kg/h) for 4 h doubled the duration of slow and REM sleep. The hypnotic effect of apomorphine was prevented by neuroleptics, such as pimozide, benzperidol and L-sulpiride, at doses which, per se, did not modify the EEG of the animals. These results suggest the existence in the CNS of DA receptors mediating sleep.

Voraciousness induced in cats by benzodiazepines.

Different benzodiazepines, when administered to fasting cats, increased both the total amount of food eaten and also the rate at which food was ingested. Moreover, when injected to foodsatiated cats, these compounds made them resume eating voraciously. Pentobarbital also stimulated food intake, but was much less potent than the benzodiazepines tested.