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

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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