大鼠地西泮身体依赖性和戒断反应与γ-氨基丁酸A型（GABAA）受体功能改变有关。

Diazepam physical dependence and withdrawal in rats is associated with alteration in GABAA receptor function.

作者信息

Toki S, Saito T, Hatta S, Takahata N

机构信息

Department of Neuropsychiatry, School of Medicine, Sapporo Medical University, Japan.

出版信息

Life Sci. 1996;59(19):1631-41. doi: 10.1016/0024-3205(96)00494-8.

DOI:10.1016/0024-3205(96)00494-8

PMID:8913328

Abstract

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.

摘要

研究了地西泮（DZP）依赖大鼠中GABAA受体复合物功能的改变及其与戒断症状变化的关系。采用药物混合食物法在雄性F344大鼠中诱导对地西泮的身体依赖。治疗停止后，观察到戒断症状，如自发性惊厥，戒断评分在DZP撤药后约39至45小时达到最大值。此外，这些戒断症状在DZP撤药后约159至168小时几乎消失。与对照大鼠相比，DZP撤药后0小时大鼠脑皮质膜囊泡中GABA刺激的36Cl-内流显著降低，DZP撤药后42小时大鼠中显著增加。在对照大鼠中观察到氟硝西泮（FZ）诱导的增强作用以及Ro 15-1788对GABA刺激的36Cl-内流的拮抗作用。在DZP撤药后0小时的大鼠中未观察到FZ增强的GABA刺激的36Cl-内流；然而，在DZP撤药后42小时和162小时的大鼠中认识到FZ的这种作用。在DZP撤药后0小时和42小时的大鼠中未认识到Ro15-1788对FZ诱导的刺激的拮抗作用，但在DZP治疗后162小时认识到，尽管不显著。在[3H]FZ与苯二氮䓬（BZ）受体结合试验中,与对照大鼠相比，DZP撤药后0小时大鼠的Bmax值显著降低，但在DZP撤药后42小时增加,DZP治疗后162小时大鼠的Bmax几乎恢复到对照水平。总之，这些结果表明，GABAA/BZ受体/CI-通道复合物的功能变化，即GABAA受体敏感性增加以及BZ受体与GABAA受体之间功能偶联受损，可能参与了长期使用DZP治疗后出现的严重戒断症状的生化机制。