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

在这个研究项目中，我们已经进行了确定药物依赖建立的共同过程，并尝试开发药物基因组疗法。尽管滥用药物会增加地尔硫卓与身体依赖小鼠脑颗粒组分结合的Bmax值，但身体依赖小鼠l型高压门控钙通道（HVCCs）功能的增加与l型HVCC α1亚基的蛋白磷酸化无关。在持续暴露于这些滥用药物的大脑皮质神经元中也观察到类似的效果。l型HVCC亚基表达上调，mRNA表达增加，提示l型HVCC的功能与其蛋白分子的增加有关，参与了身体依赖的发展。长期服用甲基苯丙胺（methamphetamine，冰毒）和可卡因后，大鼠大脑皮层和大脑皮层内[^3H]二硫卓结合Kd值降低，但l型HVCC亚基表达无变化。在动物模型中，脑室内注射硝苯地平和丹曲林可消除甲基苯丙胺/可卡因的奖赏效应，增强l型HVCC功能。在大脑皮层神经元中，硝苯地平和丹曲林也能消除冰毒和可卡因诱导的l型HVCC功能的改变。此外，持续暴露于MET和可卡因显著增强了ryanodine诱导的fura-2预负荷大脑皮质神经元钙振荡的上调，表明持续暴露于MET和可卡因增强了ryanodine受体的功能，钙通过这种功能诱导钙释放。细胞内钙动力学的这些变化被认为参与了冰毒和可卡因的心理依赖。此外，滥用药物对ryanodine受体拮抗剂对l型HVCC功能改变的不同反应可能提示生理和心理依赖的不同发病机制。少

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