DIAZEPAM PHYSICAL-DEPENDENCE AND WITHDRAWAL IN RATS IS ASSOCIATED WITH ALTERATION IN GABA(A) RECEPTOR FUNCTION

Alteration in the function of the GABA(A) receptor complex and its rel ation to changes in withdrawal signs in diazepam (DZP)-dependent rats were studied. Physical dependence on DZP was induced in male F344 rats by using the drug-admired food method. After cessation of treatment, withdrawal signs such as spontaneous convulsions were observed and wit hdrawal scores were maximal at 39 similar to 45 hr after the DZP withd rawal. Furthermore, these withdrawal signs almost disappeared by 159 s imilar to 168 hr after the DZP withdrawal. GABA-stimulated Cl-36(-) in flux into cerebral cortical membrane vesicles was significantly decrea sed in rats 0 hr after DZP withdrawal and significantly increased in r ats 42 hr after DZP withdrawal compared with control rats. Flunitrazep am (FZ)-induced potentiation and an antagonistic effect of Ro15-1788 o n GABA-stimulated Cl-36(-) influx were observed in control rats. No FZ -potentiated GABA-stimulated Cl-36(-) influx was observed in rats 0 hr after DZP withdrawal; however, such an effect of FZ was recognized in rats 42 hr and 162 hr after DZP withdrawal. No antagonistic effect of Ro15-1788 on the FZ-induced stimulation was recognized in rats 0 hr a nd 42 hr after DZP withdrawal, but was recognized at 162 hr after DZP treatment, although it was not significant. In a [H-3]FZ assay of bind ing to benzodiazepine (BZ) receptors, Bmax values were significantly d ecreased in rats 0 hr after DZP withdrawal, but increased at 42 hr aft er DZP withdrawal, compared with control rats. Bmax had almost returne d to the control level at 162 hr after DZP treatment rats. In conclusi on, these results indicate that functional changes in the GABA(A)/BZ r eceptor/Cl- channel complex, i.e. increased sensitivity in GABA(A) rec eptors and impairment in the functional coupling between BZ receptors and GABA(A) receptors, may possibly be involved in the biochemical mec hanism of the severe withdrawal symptoms appearing after chronic treat ment with DZP.