Ohkuma S, Katsura M, Tsujimura A
Department of Pharmacology, Kawasaki Medical School, Kurashiki, Japan.
Life Sci. 2001 Feb 2;68(11):1215-22. doi: 10.1016/s0024-3205(00)01031-6.
Mechanisms for formation of drug dependence and expression of withdrawal syndrome have not fully clarified despite of huge accumulation of experimental and clinical data at present. Several clinical features of withdrawal syndrome are considered to be common among patients with drug dependence induced by different drugs of abuse. One of them is anxiety. Recent investigations have revealed that diazepam binding inhibitor (DBI), a peptide consisting of 87 amino acids with molecular weight of about 10 kDa, serves as an inverse agonist for benzodiazepine (BZD) receptors with endogenously anxiogenic potential. These lines of data suggest that cerebral DBI expression in brain may participates in formation of drug dependence and/or emergence of withdrawal syndrome. Based on this working hypothesis, we have examined DBI expression in the brain derived from mice depended on alcohol (ethanol), nicotine, and morphine to investigate functional relationship between cerebral DBI expression and drug dependence. Cerebral DBI expression significantly increases in animals with drug dependence induced by these drugs, and in the cases of nicotine- and morphine-dependent mice concomitant administration of antagonists for nicotinic acetylcholine and opioid receptors, respectively, abolished the increase. Abrupt cessation of administration of drugs facilitated further increase in DBI expression. Therefore, these alterations in DBI expression have close relationship with formation of drug dependence and/or emergence of withdrawal syndrome, and are considered to be a common biochemical process in drug dependence induced by different drugs of abuse. Finding and elucidation of mechanisms for common biochemical alterations among drug dependence may provide a clue to clarify mechanisms for formation of drug dependence and/or emergence of withdrawal syndrome.
尽管目前已有大量的实验和临床数据积累，但药物依赖的形成机制和戒断综合征的表现尚未完全阐明。戒断综合征的一些临床特征被认为在不同滥用药物所致的药物依赖患者中是常见的。其中之一是焦虑。最近的研究表明，地西泮结合抑制剂（DBI）是一种由87个氨基酸组成、分子量约为10 kDa的肽，作为苯二氮䓬（BZD）受体的反向激动剂，具有内源性致焦虑潜力。这些数据表明，脑中的DBI表达可能参与药物依赖的形成和/或戒断综合征的出现。基于这一工作假设，我们检测了依赖酒精（乙醇）、尼古丁和吗啡的小鼠脑中的DBI表达，以研究脑内DBI表达与药物依赖之间的功能关系。在这些药物所致药物依赖的动物中，脑内DBI表达显著增加，而在尼古丁依赖和吗啡依赖的小鼠中，分别同时给予烟碱型乙酰胆碱受体拮抗剂和阿片受体拮抗剂可消除这种增加。突然停药会促使DBI表达进一步增加。因此，DBI表达的这些变化与药物依赖的形成和/或戒断综合征的出现密切相关，被认为是不同滥用药物所致药物依赖中的一个共同生化过程。发现并阐明药物依赖中常见生化改变的机制可能为阐明药物依赖的形成机制和/或戒断综合征的出现提供线索。
