Effects of ZK 93 426, a β-carboline benzodiazepine receptor antagonist on night sleep pattern in healthy male volunteers

Abstract

The β-carboline ZK 93 426, a benzodiazepine-antagonist with weak inverse agonist activity, was administered intravenously to human volunteers at a dose of 0.04mg/kg when they initially reached slow-wave sleep during their night's sleep. Eight subjects, subjected to half a night of sleep withdrawal, took part in the study, which was performed according to a double-blind, placebo-controlled, cross-over design. Sleep parameters as determined by electroencephalography, actometry (wrist actometer) and temperature (rectal thermometer) were monitored for the whole night. Vital functions (blood pressure and heart rate) as well as subjectively experienced effects via visual analogue scales were evaluated and blood samples for hormone plasma level estimation were taken before and after sleep. ZK 93 426 was well tolerated. Sleep parameters were reduced under the influence of the drug indicating a stimulant effect. Slow wave sleep (sleep stages 3 and 4) was significantly reduced in favour of light sleep stages 1 and 2 during the first 30 min after the administration of ZK 93 426 (P=0.02). In keeping with these findings subjects exhibited a significantly (P<0.02) elevated number and intensity of movements during the first 90 min after the β-carboline injection. Effects on self-ratings, in body temperature and on hormonal changes were not found. It is assumed that the benzodiazepine-antagonist ZK 93 426 is able to induce activation and disturb sleep via modulation of GABAergic transmission mainly by benzodiazepine receptor blocking properties. There was not sufficient evidence to support the hypothesis that a putative benzodiazepine-like endogenous ligand at the benzodiazepine receptor which may play a major role in the induction and continuation of physiological night's sleep can be antagonized by benzodiazepine receptor antagonists.