Methamphetamine induces Shati/Nat8L expression in the mouse nucleus accumbens via CREB- and dopamine D1 receptor-dependent mechanism

<div><p><i>Shati/Nat8L</i> significantly increased in the nucleus accumbens (NAc) of mice after repeated methamphetamine (METH) treatment. We reported that <i>Shati/Nat8L</i> overexpression in mouse NAc attenuated METH-induced hyperlocomotion, locomotor sensitization, and conditioned place preference. We recently found that <i>Shati/Nat8L</i> overexpression in NAc regulates the dopaminergic neuronal system via the activation of group II mGluRs by elevated <i>N</i>-acetylaspartylglutamate following <i>N-</i>acetylaspartate increase due to the overexpression. These findings suggest that <i>Shati/Nat8L</i> suppresses METH-induced responses. However, the mechanism by which METH increases the <i>Shati/Nat8L</i> mRNA expression in NAc is unclear. To investigate the regulatory mechanism of <i>Shati/Nat8L</i> mRNA expression, we performed a mouse <i>Shati/Nat8L</i> luciferase assay using PC12 cells. Next, we investigated the response of METH to <i>Shati/Nat8L</i> 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 <i>Shati/Nat8L</i> promoter to induce the <i>Shati/Nat8L</i> mRNA expression. Furthermore, the dopamine D1 receptor antagonist SCH23390, but not the dopamine D2 receptor antagonist sulpiride, inhibited the upregulation of <i>Shati/Nat8L</i> and CREB activities in the mouse NAc slices. Thus, the administration of the dopamine D1 receptor agonist SKF38393 increased the <i>Shati/Nat8L</i> mRNA expression in mouse NAc. These results showed that the <i>Shati/Nat8L</i> 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.</p></div>