RAPID DOWN-REGULATION OF [H-3] ZOLPIDEM BINDING TO RAT-BRAIN BENZODIAZEPINE RECEPTORS DURING FLURAZEPAM TREATMENT

In a previous study, it was found that down-regulation of benzodiazepine (BZ) binding in rats treated 4 weeks with flurazepam was relatively greater and more widespread when measured with [H-3]zolpidem, a selective 'BZ(1) receptor' ligand, than that measured with the non-selective ligand, [H-3]flunitrazepam. In the present study, the time course for down-regulation of [H-3]zolpidem binding was studied in rats treated with flurazepam. [H-3]Zolpidem binding was also studied in rats given a midazolam treatment shown to cause tolerance. Rats were chronically treated with flurazepam for 1 or 2 weeks, or with midazolam for 3 weeks, then killed immediately after the treatment. Another group of rats was acutely treated with desalkyl-flurazepam and killed 30 min later. after 2 weeks of flurazepam treatment, the B-max, of [H-3]zolpidem binding was decreased by 22% in cerebral cortex, 26% in cerebellum and 33% in hippocampus, with no change in the K-d in any region. After 1 week of flurazepam treatment, the B-max was decreased by 23% in cerebellum and 14% in hippocampus, but not changed in cerebral cortex. The K-d was increased in cerebral cortex, but not in cerebellum or hippocampus. Neither the B-max nor the K-d of [H-3]zolpidem binding was affected by acute desalkyl-flurazepam treatment, or by 3 weeks of midazolam treatment. These results, in combination with previous findings, which showed no change in [H-3]flunitrazepam binding after 1 or 2 week flurazepam treatment, and no change in cerebellum even after the 4 week treatment, may indicate a shift in BZ receptor subtypes in flurazepam-tolerant rats. Such a shift could be based on possible changes in the subunit composition or conformation of GABA(A)/BZ receptors after 1 or 2 week flurazepam treatment.