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Functional alteration in high voltage-gated calcium channels in drug dependence and elucidation of its mechanisms.

药物依赖性高压门控钙通道的功能改变及其机制的阐明。

基本信息

批准号：
14570095
负责人：
KATSURA Masashi
金额：
$ 2.3万
依托单位：
Kawasaki Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

Neuropharmacological mechanisms underlying development of drug dependence and withdrawal syndrome remain unclear at present. Several clinical features of withdrawal syndrome are considered to be common(i.e. anxiety) among patients with drug dependence induced by different drugs of abuse. In the present study, we have investigated functional alterations in diazepam binding inhibitor(DBI), an endogenous anxiogenic neuropeptide, in drug dependence and its withdrawal symptom. The levels of DBI protein and its mRNA significantly increased in the brains from mice dependent on alcohol, nicotine and morphine, and abrupt cessation of these drugs facilitated further increase in DBI 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 KC1(30mM)-induced[^<45>Ca^<2+>]influx and enhanced expression of α1 and α2/δ1 subunits for L-type high voltage-gated Ca^<2+> channels(HVCCs). In addition, the increase in DBI expression by drugs of abuse was completely blocked by L-type HVCC inhibitors. However, the increases in expression of L-type HVCCs after sustained exposures to drugs of abuse were not abolished by inhibitors for protein kinase A,C and CaM kinase II, respectiverly. These data indicate that up-regulation of L-type HVCCs, which causes increase in DBI expression, is considered to be a common biochemical process in drug dependence induced by different drugs of abuse.

药物依赖和戒断综合征的神经药理学机制目前尚不清楚。戒断综合征的几个临床特征（即焦虑）被认为是由不同滥用药物引起的药物依赖患者的常见特征。在本研究中，我们研究了内源性焦虑神经肽地西泮结合抑制剂（DBI）在药物依赖及其戒断症状中的功能变化。酒精、尼古丁和吗啡依赖小鼠脑中DBI蛋白及其mRNA水平显著增加，突然停止这些药物有助于DBI表达的进一步增加。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可显著增加KCl（30 mM）诱导的[^<45>Ca^2+]内流，并增强L型高压门控Ca^2+通道（HVCCs）α1和α2/δ1亚基的表达。此外，由药物滥用引起的DBI表达的增加被L型HVCC抑制剂完全阻断。然而，持续暴露于药物滥用后L型HVCCs表达的增加并没有被蛋白激酶A、C和CaM激酶II抑制剂分别消除。这些数据表明，上调L型HVCC，这导致DBI表达的增加，被认为是一个共同的生化过程中的药物依赖性诱导的不同药物滥用。