Pharmacological basis for management of drug dependence
Pharmacological basis for management of drug dependence
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DOI：
10.1196/annals.1316.071
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Ohkuma, S
中科院分区：
文献类型：
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作者：
Katsura, M;Ohkuma, S
药物依赖和戒断综合征的神经化学机制尚不清楚。戒断综合征的几个临床特征，如焦虑，被认为是常见的药物依赖患者由不同的药物滥用。在本研究中，我们调查是否安定结合抑制剂（DBI），内源性焦虑神经肽，参与与药物依赖及其戒断症状的焦虑。当我们检查依赖酒精、尼古丁和吗啡的小鼠的大脑时，我们观察到DBI蛋白及其mRNA的水平显著增加。突然停止这些药物促进DBI表达的进一步增加。在尼古丁和吗啡依赖小鼠的情况下，同时给予烟碱乙酰胆碱和μ阿片受体的特异性拮抗剂，分别取消了表达的增加。在持续暴露于这些药物并将其从培养基中去除后，在神经元中观察到类似的DBI表达模式。持续暴露于滥用药物的神经元显著增加KCl（30 mM）诱导的Ca-45（2+）内流和L型高压门控Ca 2+通道（HVCCs）α 1亚单位的表达。此外，DBI表达的增加被L型HVCC抑制剂完全阻断。因此，这些DBI表达的改变，介导的Ca 2+通过上调的L型HVCCs的增加流入，是密切相关的药物依赖和/或其戒断综合征，并被认为是一个共同的生化过程中的一部分，药物依赖诱导的不同药物滥用。
Neurochemical mechanisms underlying development of drug dependence and withdrawal syndrome remain unclear. Several clinical features of withdrawal syndrome, such as anxiety, are considered to be common among patients with drug dependence induced by different drugs of abuse. In the present study, we investigated whether diazepam-binding inhibitor (DBI), an endogenous anxiogenic neuropeptide, participates in the anxiety associated with drug dependence and its withdrawal symptoms. When we examined brain from mice dependent on alcohol, nicotine, and morphine, we observed that the levels of DBI protein and its mRNA significantly increased. Abrupt cessation of these drugs facilitated further increases in DBI expression. In the cases of nicotine- and morphine-dependent mice, concomitant administration of specific antagonists for nicotinic acetylcholine and mu-opioid receptors, respectively, abolished the increased expression. Similar patterns of DBI expression were observed in the neurons after sustained exposure to these drugs and its removal from culture medium. Sustained exposure of the neurons to abused drugs significantly increased the KCl (30 mM)-induced Ca-45(2+) influx and enhanced expression of alpha 1 subunits for L-type high voltage-gated Ca2+ channels (HVCCs). In addition, the increase in DBI expression was completely blocked by L-type HVCC inhibitors. Therefore, these alterations in DBI expression, mediated via increased influx of Ca2+ through upregulated L-type HVCCs, are closely related to drug dependence and/or its withdrawal syndrome and are considered to be part of a common biochemical process in drug dependence induced by different drugs of abuse.