Chronic exposure to Ro 15-1788: differential effect on flunitrazepam binding to cortex and hippocampus

The time course of changes in specific [3H]flunitrazepam binding following 2 weeks of treatment with the benzodiazepine antagonist Ro 15-1788 (2.7 and 4 mg/kg per day in drinking water) was studied in the rat neocortical and hippocampal synaptosomal membranes. Such a treatment produced regional increases in the density of benzodiazepine sites, which remained for up to 24 and 48 h after drug withdrawal in the hippocampus and cortex, respectively; the dissociation constant (Kd) was unchanged. In addition, a significant reduction in GABA enhanced [3H]flunitrazepam binding to cortical, but not to hippocampal, membranes from Ro 15-1788-treated animals was found 72 h after drug withdrawal. These data show that there is a regional difference in responses of the GABA/benzodiazepine receptor complex following chronic in vivo exposure to Ro 15-1788 and that, beside the increases in the maximal binding (Bmax) of [3H]flunitrazepam the coupling between the GABA and the benzodiazepine recognition sites was also affected.