An attempt to develop pharmacogenomic therapy and prevention of drug dependence.

尝试开发药物基因组疗法和预防药物依赖。

基本信息

批准号：
15390175
负责人：
OHKUMA Seitaro
金额：
$ 8.45万
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 (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

This research project has been carried out to develop pharmacogenomic therapy and prevention of drug dependence.Chronic administrations of ethanol, morphine, and nicotine produced increase of Bmax values of [^3H] diltiazem binding to the particulate fractions from animal cerebral cortex and increased expressions of α1C and α1D subunits of L-type high voltage-gated calcium channels (HVCCs) in animal cerebral cortex. Similarly, long-term exposure of cerebrocortical neurons in primary culture to these drugs of abuse also increased Bmax values of [^3H]diltiazem binding and expressions of α1C and α1D subunits of L-type HVCCs. These alterations of L-type HVCC subunit expressions followed the increased their mRNA expressions, suggesting that the L-type HVCC functions associated with increase in their protein molecules are involved in development of physical dependence.On the other hand, methamphetamine(MET) and cocaine produced decreased Kd value of binding with no changes of L-type HVCC subu … More nit expressions in animal cerebral cortex and cerebral cortical neurons. In conditioned place preference(CPP) test, intraventricular administration of nifedipine and dantrolene abolished increased CPP by MET and enhanced L-type HVCC functions described above. In cerebrocortical neurons, exposure to nifedipine and dantrolene also abolished the alteration of L-type HVCC functions induced by MET and cocaine, while the changes of L-type HVCCs associated with increased expressions of their subunits were not affected by similar treatments. In addition, sustained exposure to MET and cocaine significantly enhanced ryanodine-induced increase of calcium oscillation in cerebrocortical neurons when examining with fura-2, suggesting the lonf-term exposure to MET and cocaine enhanced ryanodine receptors through which calcium-induced calcium release. These changes in intracellular calcium dynamics are considered to participate in psychological dependence by MET and cocains. In addition, the differences in L-type HVCC subunit expression patterns and in response of L-type HVCC subunit expression to dantrolene are considered to suggest different pathogenesis between physical and psychological dependence. Less

该研究项目的目的是开发药物基因组疗法和预防药物依赖。长期服用乙醇、吗啡和尼古丁会导致[^3H]地尔硫卓与动物大脑皮层颗粒部分结合的 Bmax 值增加，并增加动物大脑皮层中 L 型高压门控钙通道 (HVCC) α1C 和 α1D 亚基的表达类似地，长期暴露于大脑皮层神经元中。这些滥用药物的原代培养物还增加了 L 型 HVCC 的 [^3H]地尔硫卓结合的 Bmax 值以及 α1C 和 α1D 亚基的表达，这些 L 型 HVCC 亚基表达的改变伴随着它们的 mRNA 表达的增加。表明 L 型 HVCC 功能与其蛋白质分子的增加相关，参与身体依赖性的发展。另一方面，甲基苯丙胺 (MET) 和可卡因产生的结合 Kd 值降低在条件性位置偏好（CPP）测试中，心室内给予硝苯地平和丹曲林消除了 MET 增加的 CPP 并增强了上述 L 型 HVCC 功能。在大脑皮质神经元中，硝苯地平和丹曲林的暴露也消除了 MET 和可卡因诱导的 L 型 HVCC 功能的改变，而与其亚基表达增加相关的 L 型 HVCC 并未受到类似治疗的影响。此外，在使用 fura-2 检查时，持续暴露于 MET 和可卡因可显着增强兰尼定诱导的大脑皮质神经元钙振荡增加，这表明 lonf-长期接触 MET 和可卡因会增强兰尼碱受体，通过钙诱导的钙释放，细胞内钙动力学的这些变化被认为参与了 MET 和可卡因的心理依赖。此外，L型HVCC亚基表达模式的差异以及L型HVCC亚基表达对丹曲林的反应被认为表明身体和心理依赖性之间的不同发病机制。