Beta-carbolines as tools in memory research: human data with the beta-carboline ZK 93426

The discovery of substances which bind with high affinity to benzodiazepine receptors but have no pharmacological effects (antagonists) or effects opposite to those of benzodiazepines (inverse agonists) have introduced a new approach to elucidating mechanisms underlying memory and other cognitive processes. Since benzodiazepines induce anterograde amnesia and sedation, these substances should show an opposite effect and so enhance memory and/or increase vigilance. In the present report we present data obtained in humans with a benzodiazepine receptor antagonist with weak inverse agonist properties, ZK 93426. The drug was given intravenously to human volunteers in double-blind, placebo-controlled designs and performance on several psychometric tests was evaluated. In a general estimation of behavioural changes volunteers experienced a stimulatory, activating effect of the drug. An improvement was observed in two cognitive tasks, the logical reasoning task and the pictures difference task, which estimate concentration and attentional processes respectively. No effects were found in a letter cancellation test or in time estimation. In another study utilizing EEG recording, we demonstrated that ZK 93426 increased wakefulness (vigilance) in healthy subjects during the daytime. The effect of ZK 93426 upon memory processes was also investigated utilizing a visual memory test and word lists. A slight improvement in some memory processes, especially long-term retrieval, was found. The present data suggest that benzodiazepine receptor antagonists with weak inverse intrinsic activity possess some effects opposite to those of benzodiazepines.