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

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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