CHANGES IN [H-3] FLUNITRAZEPAM BINDING IN THE BRAIN OF RATS MADE TOLERANT TO AND DEPENDENT UPON PENTOBARBITAL

Changes in benzodiazepine binding sites labeled by [H-3]flunitrazepam (FNZ) in twenty discrete brain regions of rats made tolerant to and de pendent upon pentobarbital were examined. Animals were rendered tolera nt by intracerebroventricular (i.c.v) infusion with pentobarbital (300 mu g/10 mu l/hr for six days) through pre-implanted cannulae connecte d to osmotic mini-pumps. The pentobarbital dependence was assessed 24 hr after abrupt withdrawal from pentobarbital. In the tolerant rats, a significant increase in [H-3]FNZ binding sites was found in layer IV of frontal cortex and the molecular layer of olfactory bulb. [H-3]FNZ binding sites in the pentobarbital dependent rats were significantly i ncreased in layers I-III and V-VI of frontal cortex, caudate-putamen, olfactory tubercle, globus pallidus and ventral pallidum, in addition to those observed in the tolerant group. There was, however, no signif icant difference in the hippocampus and several regions in the hindbra in in either pentobarbital-treated group. Taken together with characte ristics of subtypes of benzodiazepine receptors and changes in GABA-be nzodiazepine receptor complexes elucidated in our previous studies, th ese findings suggest that both types of benzodiazepine receptors are i nvolved in the development of pentobarbital intoxication mediated by G ABA(A) receptors.