Interaction of barbiturates with benzodiazepine receptors in the central nervous system

The interaction of barbiturates with benzodiazepine receptors was studied in extensively washed membrane preparations from rat brain. Sedative/hypnotic and anesthetic barbiturates such as pentobarbital, and convulsant barbiturates such as DMBB, enhanced [³H]diazepam binding in a stereospecific fashion. Freezethawing of membranes resulted in a decrease in the potency of barbiturates to enhance [³H]diazepam binding, while the maximum response to barbiturates remained unchanged. Significant differences in both the potency and maximum enhancement of [³H]diazepam binding by pentobarbital was observed among brain regions. The rank order potency of pentobarbital in different brain regions was: cerebellum > cortex > hippocampus, while the rank order efficacy of pentobarbital in these brain regions was reversed. The effects of a combination of anesthetic and/or convulsant barbiturates on [³H]diazepam binding suggested that these compounds function as partial agonists while a combination of anesthetic or convulsant barbiturates with phenobarbital suggested that the latter compound antagonized the actions of both anesthetic and convulsant barbiturates. The convulsant benzodiazepine Ro-5-3663 and inosine were more potent as inhibitors of pentobarbital-enhanced than basal (non-pentobarbital enhanced) [³H]diazepam binding. Solubilization of benzodiazepine receptors with Lubrol-PX resulted in a complete loss of barbiturate enhanced [³H]diazepam binding, and greater than a 75% loss in efficacy in the remaining (insoluble receptor) tissue.