Anxiogenic and non-anxiogenic benzodiazepine antagonists

Abstract

Benzodiazepines are widely used anxiolytic and anticonvulsant drugs, and brain receptors for these drugs have been characterized by Möhler and Okada¹ and Squires and Braestrup². Recently, substances that antagonize benzodiazepine binding to brain receptors have been discovered^3,4. These benzodiazepine antagonists were shown to block the central effects of benzodiazepines and particularly their anticonvulsive properties^3,5,6. Two such antagonists, Ro 15-1788 (an imidazodiazepine) and methyl β-carboline-3-carboxylate (β-CCM), have recently been shown to have different intrinsic pharmacological properties. β;-CCM, injected into baboons, cats, mice and rats, is a convulsant^6–8, whereas Ro 15-1788 lacks such an activity. Thus, the separation of convulsant and non-convulsant antagonists has been proposed⁸. We suggest here that a sub-classification of antagonists is also valid at the behavioural level, based on a conflict model in mice. We show that Ro 15-1788 and β-CCM antagonize the anxiolytic effect of benzodiazepines. In addition, we find that, when injected alone, Ro 15-1788 has no anxiogenic effects while β-CCM has anxiogenic properties. We therefore propose that β-CCM is an anxiogenic convulsant benzodiazepine antagonist and that Ro 15-1788 is a non-anxiogenic non-convulsant benzodiazepine antagonist.