Chan A W, Schanley D L, Leong F W, Casbeer D
Pharmacol Biochem Behav. 1982 Dec;17(6):1239-44. doi: 10.1016/0091-3057(82)90127-7.
The previously-observed attenuation of withdrawal reactions in mice (group B) fed an ethanol diet containing chlordiazepoxide (CDP) was not due to a difference in the rate of disappearance of blood ethanol levels during chronic diet treatment in group B compared to mice which received only the ethanol diet (group A). Injection of group A mice with CDP or N-demethyl CDP (10 mg/kg) at the time of diet withdrawal did not result in any significant attenuation of withdrawal scores. Injection of the lactam metabolite of CDP (LCDP; 10 mg/kg) resulted in significantly attenuated withdrawal scores at 4 and 6 hr only, but the pattern of withdrawal scores were different from that for group B mice. Moreover, blood LCDP level, in mice injected with LCDP, at 4 hr was at least five times higher than that attained in group B mice (from diet containing CDP). These results support our previous conclusion that the presence of major metabolites of CDP during withdrawal could only account for a minor contribution to the protective effect. Mice in A and B did not differ in the degree of functional tolerance which developed as a result of ethanol intake. Thus, there was an apparent dissociation between tolerance and physical dependence in the mice which had consumed the CDP/ethanol diet. The magnitude of decrease of GABA levels in the cerebellum and cerebral cortex at 4 hr after withdrawal also did not differ between the two groups, suggesting the reduction in GABA levels could not be correlated with the intensity of withdrawal signs.
先前观察到，喂食含氯氮䓬（CDP）乙醇饮食的小鼠（B组）戒断反应减弱，这并非是由于与仅接受乙醇饮食的小鼠（A组）相比，B组在慢性饮食治疗期间血液乙醇水平消失速率存在差异所致。在饮食戒断时给A组小鼠注射CDP或N - 去甲基CDP（10 mg/kg），并未导致戒断评分有任何显著降低。仅在注射CDP的内酰胺代谢物（LCDP；10 mg/kg）后4小时和6小时，戒断评分显著降低，但戒断评分模式与B组小鼠不同。此外，注射LCDP的小鼠在4小时时血液中LCDP水平至少比（从含CDP饮食中获取的）B组小鼠高五倍。这些结果支持我们先前的结论，即戒断期间CDP主要代谢物的存在对保护作用的贡献较小。A组和B组小鼠因摄入乙醇而产生的功能性耐受程度并无差异。因此，食用CDP/乙醇饮食的小鼠在耐受性和身体依赖性之间存在明显的分离。两组在戒断后4小时小脑和大脑皮质中GABA水平降低的幅度也没有差异，这表明GABA水平的降低与戒断症状的强度无关。
