Anxiogenic and non-anxiogenic benzodiazepine antagonists.

Benzodiazepines are widely used anxiolytic and anticonvulsant drugs, and brain receptors for these drugs have been characterized by Möhler and Okada and Squires and Braestrup. Recently, substances that antagonize benzodiazepine binding to brain receptors have been discovered. These benzodiazepine antagonists were shown to block the central effects of benzodiazepines and particularly their anticonvulsive properties. Two such antagonists, Ro 15-1788 (an imidazodiazepine) and methyl beta-carboline-3-carboxylate (beta-CCM), have recently been shown to have different intrinsic pharmacological properties. beta-CCM, injected into baboons, cats, mice and rats, is a convulsant, whereas Ro 15-1788 lacks such an activity. Thus, the separation of convulsant and non-convulsant antagonists has been proposed. We suggest here that a subclassification of antagonists is also valid at the behavioural level, based on a conflict model in mice. We show that Ro 15-1788 and beta-CCM antagonize the anxiolytic effect of benzodiazepines. In addition, we find that, when injected alone, Ro 15-1788 has no anxiogenic effects while beta-CCM has anxiogenic properties. We therefore propose that beta-CCM is an anxiogenic convulsant benzodiazepine antagonist and that Ro 15-1788 is a non-anxiogenic non-convulsant benzodiazepine antagonist.