Identification of common biological markers 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 biological markers underlying establishment of drug dependence and an attempt to develop pharmacogenomic therapy.Functional alterations in L-type high voltage-gated calcium channels (Cav1) after short-term (24h) exposure of mouse cerebrocortical neurons to drugs of abuse were examined as compared with those in psychological dependent mouse brains. KC1 (30 mM)-stimulated [^<45>Ca^<2+>] influx into the neurons increased with increasing the duration of the drugs exposure and its concentrations. This enhancement was completely abolished by Cav1 inhibitors, and antagonists for ryanodine and IP_3 receptors. Cav1.2 and Cav α2-δ proteins were increased in abused drugs-treated neurons. Increased binding of [^<3>H]PN200-110 after 24 h exposure to drugs of abuse was due to decreased Kd value. Similar changes in the binding parameters and protein expressions were obtained in cerebral cortices as well as nucleus accumbens fro … More m psychological dependent mice. These results indicate that stimulation of calcium-induced calcium release by ryanodine receptors and subsequent activations of IP_3 receptors induces Cav1 up-regulation.Furthermore, we examined the functional involvement of accessory proteins of Cav 3 subunits in ethanol (EtOH)-induced Cav1 up-regulation. Short-term exposure of the neurons to EtOH significantly increased in Cav β3 subunit levels, whereas Cav β1, β2 and β4 subunits showed no changes. High potassium-stimulated [^<45>Ca^<2+>] influx into the neurons significantly increased by EtOH exposure and this increase was not observed in the neurons pretreated with morpholino oligomers specific for Cav β3 subunits. Decreased Kd value of [^3H] P: N200-110 after EtOH exposure was also abolished by Cav β3 subunits knockdown. Similar changes in protein expressions were obtained in cerebral cortices from psychological dependent mice. These results indicate that short-term exposure of the neurons to EtOH up-regulates Cav1 functions via increased expression of Cav β3 subunit proteins in the neuronal membrane. Less