Abstract
Shati/Nat8L significantly increased in the nucleus accumbens (NAc) of mice after repeated methamphetamine (METH) treatment. We reported that Shati/Nat8L overexpression in mouse NAc attenuated METH-induced hyperlocomotion, locomotor sensitization, and conditioned place preference. We recently found that Shati/Nat8L overexpression in NAc regulates the dopaminergic neuronal system via the activation of group II mGluRs by elevated N-acetylaspartylglutamate following N-acetylaspartate increase due to the overexpression. These findings suggest that Shati/Nat8L suppresses METH-induced responses. However, the mechanism by which METH increases the Shati/Nat8L mRNA expression in NAc is unclear. To investigate the regulatory mechanism of Shati/Nat8L mRNA expression, we performed a mouse Shati/Nat8L luciferase assay using PC12 cells. Next, we investigated the response of METH to Shati/Nat8L expression and CREB activity using mouse brain slices of NAc, METH administration to mice, and western blotting for CREB activity of specific dopamine receptor signals in vivo and ex vivo. We found that METH activates CREB binding to the Shati/Nat8L promoter to induce the Shati/Nat8L mRNA expression. Furthermore, the dopamine D1 receptor antagonist SCH23390, but not the dopamine D2 receptor antagonist sulpiride, inhibited the upregulation of Shati/Nat8L and CREB activities in the mouse NAc slices. Thus, the administration of the dopamine D1 receptor agonist SKF38393 increased the Shati/Nat8L mRNA expression in mouse NAc. These results showed that the Shati/Nat8L mRNA was increased by METH-induced CREB pathway via dopamine D1 receptor signaling in mouse NAc. These findings may contribute to development of a clinical tool for METH addiction.
Highlights
Addiction and abuse of drugs such as methamphetamine (METH) are social problems worldwide [1]
We found that the transcriptional factors cAMP response element-binding protein (CREB) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) may bind to the promoter region of Shati/Nat8L and that the induction of the Shati/Nat8L mRNA expression is regulated by CREB via the activation of dopamine D1 receptors; we discussed about how a clarification of the regulatory mechanism of Shati/Nat8L may contribute to the development of a clinical tool for METH addiction
It was reported that NAA produced from Shati/Nat8L was associated with Canavan disease [24]
Summary
Addiction and abuse of drugs such as methamphetamine (METH) are social problems worldwide [1]. Regulatory mechanism by methamphetamine for Shati/Nat8L expression for Medical Research and Development (http:// www.amed.go.jp/en/) (16mk0101076h0001) to Atsumi Nitta, Kobayashi International Foundation, (http://www.kisf.or.jp/english/index.html) to Atsumi Nitta. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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