Bidirectional nature of benzodiazepine receptor ligands extends to effects on vigilance.

Abstract

The classification of benzodiazepine receptor ligands into agonists, antagonists and inverse agonists is based on biochemical, electrophysiological and behavioural evidence. Agonists potentiate the effects of gamma-aminobutyric acid (GABA) and exhibit anxiolytic, anticonvulsant, hypnotic, amnesic and muscle-relaxant properties; inverse agonists show mirror-image effects in that they may be convulsant and anxiogenic and may increase muscle tone. Antagonists antagonise the effects of both agonists and inverse agonists. Some of the most interesting ligands, however, are those substances with actions intermediate between either those of the agonists and the antagonists, or between those of the antagonists and the inverse agonists. These partial agonists and partial inverse agonists possess only some of the properties of the agonists and inverse agonists, respectively. The present experiments show that the agonist and inverse agonist properties of benzodiazepine receptor ligands can also be revealed in an animal continuous attention task in which rats were required to detect a brief signal during which operation of a lever was rewarded by food. Benzodiazepines and a beta-carboline benzodiazepine receptor agonist, ZK 93423, disrupted performance of this task, as did the antimuscarinic substance, scopolamine. Another beta-carboline, ZK 91296, which has anxiolytic and anticonvulsant properties like benzodiazepines, did not affect performance of the continuous attention task, demonstrating a separation of anxiolytic and sedative properties of such substances. A partial inverse agonist beta-carboline, FG 7142, was able to antagonise the disruptive effects of scopolamine on this task, as was, to a smaller extent, the antagonist ZK 93426. These results are discussed in terms of vigilance-enhancing properties of the inverse agonist beta-carbolines, and the possibility that such vigilance-enhancing effects might contribute to improvement of performance in learning tasks.