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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

本研究旨在开发药物基因组治疗和预防药物依赖。长期给予乙醇、吗啡和尼古丁可使动物大脑皮层颗粒组分结合的地尔硫卓的Bmax增加，并增加动物大脑皮层L型高电压门控钙通道(HvCC)α1C和α1D亚单位的表达。同样，长期暴露于这些药物的原代培养的大脑皮层神经元也增加了L型HvCC[~(3 H)]地尔硫卓结合的Bmax以及α1C和α1D亚单位的表达。另一方面，甲基苯丙胺和可卡因使…结合Kd值降低，而L型HvCC Subu DNA无明显变化NIT在动物大脑皮层和大脑皮层神经元中的表达较多。在条件性位置偏爱(CPP)实验中，脑室注射硝苯地平和丹曲林可消除MET引起的CPP升高，并增强上述L式高压心脏收缩功能。在大脑皮层神经元中，硝苯地平和丹曲林可完全消除甲硫氨酸和可卡因引起的L式高压收缩细胞功能的改变，而与其亚单位表达增加相关的L式高压收缩能力的改变不受类似处理的影响。此外，用Fura-2检测时，持续暴露于Met和可卡因可显著增强Ryanodine诱导的大脑皮层神经元钙振荡的增加，提示长期暴露于Met和可卡因可增强Ryanodine受体，而Ryanodine受体是通过这种受体诱导钙释放的。这些细胞内钙动力学的变化被认为参与了多效唑和可卡因的心理依赖。此外，L亚基表达模式的不同以及L亚基表达对丹曲林反应的不同提示了生理依赖和心理依赖之间的不同发病机制。较少