Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan.
Curr Neuropharmacol. 2011 Mar;9(1):104-8. doi: 10.2174/157015911795017362.
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-α (TNF-α) 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-α. Transfection of the vector containing shati cDNA into PC12 cells, dramatically induced the expression of shati and TNF-α mRNA, accelerated dopamine uptake, and inhibited the methamphetamine-induced decrease in dopamine uptake. These effects were blocked by neutralizing TNF-α. These results suggest that the functional roles of shati in methamphetamine-induced behavioral changes are mediated through the induction of TNF-α expression which inhibits the methamphetamine-induced increase of dopamine overflow and decrease in dopamine uptake.
滥用药物导致依赖的能力可以看作是一种神经可塑性。最近，我们已经证明肿瘤坏死因子-α（TNF-α）增加多巴胺摄取并抑制安非他命诱导的依赖。此外，我们还使用 PCR 选择 cDNA 消减法鉴定了在安非他命处理的小鼠伏隔核中的一种新分子“shati”，并阐明它参与了安非他命依赖的发展：用 shati 反义寡核苷酸（shati-AS）处理，抑制 shati mRNA 的表达，增强了安非他命诱导的过度运动、敏化和条件性位置偏爱。此外，shati-AS 阻断 shati mRNA 增强了安非他命诱导的伏隔核多巴胺溢出增加和多巴胺摄取减少。有趣的是，shati-AS 的处理也抑制了 TNF-α 的表达。将包含 shati cDNA 的载体转染到 PC12 细胞中，显著诱导了 shati 和 TNF-α mRNA 的表达，加速了多巴胺摄取，并抑制了安非他命诱导的多巴胺摄取减少。这些效应被中和 TNF-α 阻断。这些结果表明，shati 在安非他命诱导的行为变化中的功能作用是通过诱导 TNF-α 表达介导的，抑制了安非他命诱导的多巴胺溢出增加和多巴胺摄取减少。
