Changes in GABAA Receptor Complex Function in Diazepam Dependent Rats

Alteration in the function of the GABAA receptor complex and its relation to changes in withdrawal signs in diazepam-dependent rats were studied. Physical dependence on diazepam was induced in male F344 rats by using the drug-admixed food method. After cessation of treatment, withdrawal signs such as spontaneous convulsions were observed and withdrawal scores were maximal at 39?45 hr after the diazepam withdrawal. Furthermore, these withdrawal signs almost disappeared by 159?168 hr after the diazepam withdrawal. Maximal stimulation of GABA-stimulated 36Cl- influx into cerebral cortical membrane vesicles was significantly decreased in rats 0 hr after diazepam withdrawal compared with control rats. Furthermore, both maximal stimulation and half maximal stimulation of GABA-stimulated 36Cl- influx were significantly increased in rats 42 hr after diazepam withdrawal compared with the control. At 162 hr after diazepam treatment, the increases in GABA-stimulated 36Cl- influx observed at 42 hr were not recognized. Flunitrazepam induced potentiation on GABA-stimulated 36Cl- influx were observed in control rats. On the other hand, flunitrazepam-potentiated GABA-stimulated 36Cl- influx was not observed in rats 0 hr after diazepam withdrawal; however, such an effect of flunitrazepam was recognized in rats 42 hr and 162 hr after diazepam withdrawal. Ethanol-induced potentiation on GABA-stimulated 36Cl- influx were observed in control rats. However, at 0 hr and 42 hr after diazepam withdrawal, ethanol-induced potentiation on GABA-stimulated 36Cl- influx were not observed. In a [3 H] flunitrazepam assay of binding to benzodiazepine receptors, Bmax values were significantly decreased in rats 0 hr after diazepam withdrawal, but increased at 42 hr after diazepam withdrawal, compared with control rats. Bmax had almost returned to the control level at 162 hr after diazepam treatment of rats.? In conclusion, these results indicate that functional changes in the GABA A/benzodiazepine rece-ptor/C1- channel complex may possibly be involved in the biochemical mechanism of the severe withdrawal symptoms appearing after chronic treatment with diazepam. Furthermore, these alterations may be related to the cross-tolerance and cross-dependence between benzodiazepine and ethanol