权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Identification of common process underlying establishment of drug dependence and an attempt to develop pharmacogenomic therapy.

确定药物依赖性建立的共同过程并尝试开发药物基因组疗法。

基本信息

批准号：
16590212
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：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

In this research project, we have been carried out to identify the common process underlying establishment of drug dependence and an attempt to develop pharmacogenomic therapy.Functional increase in L-type high voltage-gated calcium channels (HVCCs) were not associated with protein phospholrylation of L-type HVCC α1 subunits in physical dependence, although the abused drugs produced increase in Bmax values of [^3H]diltiazem binding to the particulate fractions from physical dependent mouse brains. Similar effects were also observed in sustained exposure of cerebral cortical neurons to these abused drugs. The up-regulation of L-type HVCC subunit expressions with increased its mRNA expressions suggest that the L-type HVCC functions associated with increase in their protein molecules are involved in development of physical dependence.Decrease in Kd value of [^3H]diltiazem binding with no changes in L-type HVCC subunit expressions were observed in cerebral cortices and cerebral cortical ne … More urons after long-term treatments with methamphetamine (METH) and cocaine. In animal models, intraventricular injection of nifedipine and dantrolene abolished rewarding effects by METH/cocaine and enhanced L-type HVCC functions. In cerebral cortical neurons, nifedipine and dantrolene also abolished the alteration of L-type HVCC functions induced by METH and cocaine. In addition, sustained exposure to MET and cocaine significantly enhanced ryanodine-induced up-regulate of calcium oscillation in fura-2 preloading cerebral cortical neurons, suggesting the sustained exposure to MET and cocaine enhanced ryanodine receptor functions through which calcium-induced calcium release. These changes in intracellular calcium dynamics are considered to participate in psychological dependence by METH and cocaine. Moreover, the different responses to ryanodine receptor antagonists on functional changes in L-type HVCC by abused drugs are considered to suggest different pathogenesis between physical and psychological dependence. Less

在这项研究中，我们一直致力于确定药物依赖建立的共同过程和开发药物基因组疗法的尝试。L型高压门控钙通道功能的增加与身体依赖下L型高压门控钙通道α1亚单位的蛋白磷酸化无关，尽管滥用药物导致物理依赖小鼠脑颗粒组分结合的[^~3H]地尔硫卓的Bmax增加。在大脑皮层神经元持续暴露于这些滥用药物中也观察到了类似的效果。L型…亚单位表达上调，其蛋白分子表达增加，提示L型HVCC功能与其蛋白分子的增加有关。在大脑皮层和大脑皮质NE中，观察到[~3H]地尔硫卓结合Kd值降低，而L型HVCC亚单位表达无变化在长期服用甲基苯丙胺(冰毒)和可卡因后，尿液会更多。在动物模型中，脑室注射硝苯地平和丹曲林可消除冰毒/可卡因的奖赏效应，并增强L式的血管紧张性心动过速功能。在大脑皮层神经元中，硝苯地平和丹曲林也可阻断冰毒和可卡因所致的L式肾小管上皮细胞收缩功能的改变。此外，持续暴露于Met和可卡因可显著增强Ryanodine诱导的Fura-2预负荷大脑皮层神经元钙振荡的上调，提示Met和可卡因持续暴露增强了Ryanodine受体的功能，而Ryanodine是通过钙诱导钙释放的。这些细胞内钙动力学的变化被认为参与了冰毒和可卡因的心理依赖。此外，Ryanodine受体拮抗剂对滥用药物引起的L型肾小管上皮细胞癌功能改变的不同反应提示了生理依赖和心理依赖的不同发病机制。较少