Roles of a Novel Molecule 'Shati' in the Development of Methamphetamine-Induced Dependence

The ability of drugs of abuse to cause dependence can be viewed as a form of neural plasticity. Recently, we have demonstrated that tumor necrosis factor-alpha (TNF-alpha) increases dopamine uptake and inhibits methamphetamine-induced dependence. Moreover, we have identified a novel molecule 'shati' in the nucleus accumbens of mice treated with methamphetamine using the PCR-select cDNA subtraction method and clarified that it is involved in the development of methamphetamine dependence: Treatment with the shati antisense oligonucleotide (shati-AS), which inhibits the expression of shati mRNA, enhanced the methamphetamine-induced hyperlocomotion, sensitization, and conditioned place preference. Further, blockage of shati mRNA by shati-AS potentiated the methamphetamine-induced increase of dopamine overflow and the methamphetamine-induced decrease in dopamine uptake in the nucleus accumbens. Interestingly, treatment with shati-AS also inhibited expression of TNF-alpha. Transfection of the vector containing shati cDNA into PC12 cells, dramatically induced the expression of shati and TNF-alpha mRNA, accelerated dopamine uptake, and inhibited the methamphetamine-induced decrease in dopamine uptake. These effects were blocked by neutralizing TNF-alpha. These results suggest that the functional roles of shati in methamphetamine-induced behavioral changes are mediated through the induction of TNF-alpha expression which inhibits the methamphetamine-induced increase of dopamine overflow and decrease in dopamine uptake.