Diazepam physical dependence and withdrawal in rats is associated with alteration in GABAA receptor function.
Alteration in the function of the GABAA receptor complex and its relation 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-admixed food method. After cessation of treatment, withdrawal signs such as spontaneous convulsions were observed and withdrawal scores were maximal at 39 approximately 45 hr after the DZP withdrawal. Furthermore, these withdrawal signs almost disappeared by 159 approximately 168 hr after the DZP withdrawal. GABA-stimulated 36Cl- influx into cerebral cortical membrane vesicles was significantly decreased in rats 0 hr after DZP withdrawal and significantly increased in rats 42 hr after DZP withdrawal compared with control rats Flunitrazepam (FZ)-induced potentiation and an antagonistic effect of Ro 15-1788 on GABA-stimulated 36Cl- influx were observed in control rats. No FZ-potentiated GABA-stimulated 36Cl- 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 and 42 hr after DZP withdrawal but was recognized at 162 hr after DZP treatment, although it was not significant. In a [3H]FZ assay of binding to benzodiazepine (BZ) receptors. Bmax values were significantly decreased in rats 0 hr after DZP withdrawal, but increased at 42 hr after DZP withdrawal, compared with control rats Bmax had almost returned to the control level at 162 hr after DZP treatment rats. In conclusion, these results indicate that functional changes in the GABAA/BZ receptor/CI- channel complex, i.e. increased sensitivity in GABAA receptors and impairment in the functional coupling between BZ receptors and GABAA receptors, may possibly be involved in the biochemical mechanism of the severe withdrawal symptoms appearing after chronic treatment with DZP.
Department of Neuropsychiatry, School of Medicine, Sapporo Medical University, Japan.
S
S
Toki
T
T
Saito
S
S
Hatta
N
N
Takahata
D000818:Animals; D001569:Benzodiazepines / Q000037:antagonists & inhibitors; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D003975:Diazepam / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D005442:Flumazenil / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism / Q000494:pharmacology; D018757:GABA Modulators / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011963:Receptors, GABA-A / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D019966:Substance-Related Disorders / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018118:Chloride Channels; D002712:Chlorides; D018757:GABA Modulators; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; D003975:Diazepam