Basic research for the treatment of psychological dependence on methamphetamine

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Repeated treatment with methamphetamine leads to an enhancement in the methamphetamine-induced dopamine release and its related behaviors. This phenomenon is called sensitization or reverse tolerance. In this study, I demonstrated the effect of N-methyl-D-aspartate(NMDA) receptor antagonist ifenprodil and κ-opioid receptor agonist TRK-820 on the development of sensitization to the methamphetamine-induced rewarding effect and dopamine release in rodents. The conditioned place preference paradigm and in vivo microdialysis assay were performed in the present study. The treatment with ifenprodil or TRK-820 abolished the enhancement of the methamphetamine-induced place preference following repeated treatment with methamphetamine. Furthermore, intra-nucleus accumbens (N.Acc.) injection of TRK-820 blocked the development of sensitization to dopamine release in the N.Acc.induced by repeated methamphetamine treatment. These findings strongly indicate that treatment with ifenprodil or TRK-820 co … More uld be highly recommended for the cure of drug dependence.On the other hand, I investigated that intra-nucleus accumbens injection of a selective protein kinase C(PKC) inhibitor chelerythrine chloride blocked the development of sensitization to dopamine release in the N.Acc.induced by repeated methamphetamine treatment. Under these conditions, the immunoreactivity of the cytosolic phosphorylated-PKC in the limbic forebrain region including the N.Acc.was slightly, but significantly increased in methamphetamine-sensitized rats. Furthermore, it should be mentioned that the protein level of NR2B subunit was significantly increased in membrane preparations of the limbic forebrain obtained from methamphetamine-sensitized rats. Moreover, methamphetamine produced prolonged PKC-dependent astrocytic activation, whereas morphine caused a reversible activation of astrocytes in in vivo and in vitro study. In conclusion, the present study provides novel evidence that the development of sensitization to the methamphetamine-induced rewarding effects may be, at least in part, linked to the increased level of PKC, NR2B subunit and PKC-dependent astrocytic activation by methamphetamine in rodents. Less