In vivo binding of beta-carbolines in mice: regional differences and correlation of occupancy to pharmacological effects.

beta-Carbolines are competitive ligands of central type benzodiazepine receptors and have been reported to display either agonist, inverse agonist, or antagonist activities in vivo. We studied the in vivo inhibition of [3H]Ro 15-1788 binding in mice by various beta-carbolines of different pharmacological profiles and found that they were all more potent in the cerebellum than in the cortex and hippocampus; their ID50 values (dose inhibiting 50% of the specific binding of [3H]Ro 15-1788) were 3 to 7 times lower in the cerebellum than in the hippocampus. The ID50 of the triazolopyridazine CL 218,872 was 2.3 times lower in the cerebellum than in the hippocampus. Thus, regional differences do not seem to explain pharmacological profile. Correlation of receptor occupancy with pharmacological effects showed that high receptor occupancy (40%) was needed to obtain the convulsant effects of the inverse agonist methyl-beta-carboline-3-carboxylate whereas intermediate receptor occupancy (30%) led to the proconflict effects and very low receptor occupancy (less than 5%) to the facilitating effects in learning and memory tasks. We also found that the selective antagonist of the sedative effects of benzodiazepines 3-(methoxycarbonyl)-amino-beta-carboline, even at high doses (20 mg/kg), did not occupy more than 70% of the benzodiazepine receptors.