Inhibitory effects of Shati/Nat8l overexpression in the medial prefrontal cortex on methamphetamine‐induced conditioned place preference in mice

Shati/Nat8l is a novel N‐acetyltransferase identified in the brain of mice treated with methamphetamine (METH). Shati/Nat8l mRNA is expressed in various brain areas, including the prefrontal cortex (PFC), where the expression level is higher than that in other brain regions. Shati/Nat8l overexpression in the nucleus accumbens (NAc) attenuates the pharmacological response to METH via mGluR3. Meanwhile, dopamine (DA) and glutamate dysregulations have been reported in the medial prefrontal cortex (mPFC) and NAc after METH self‐administration and during reinstatement. However, the mechanism, the reward system, and function of Shati/Nat8l in the mPFC is unclear. Here, we injected an adeno‐associated virus (AAV) vector containing Shati/Nat8l into the mPFC of mice, to overexpress Shati/Nat8l in the mPFC (mPFC‐Shati/Nat8l). Interestingly, the METH‐induced conditioned place preference (CPP) was attenuated in the mPFC‐Shati/Nat8l mice, but locomotor activity was not. Additionally, immunohistochemical results from mice that were injected with AAV‐GFP showed fluorescence in the mPFC and other brain regions, mainly the NAc, indicating an mPFC‐NAc top‐down connection. Finally, in vivo microdialysis experiments revealed that Shati/Nat8l overexpression in the mPFC reduced extracellular DA levels and suppressed the METH‐induced DA increase in the NAc. Moreover, decreased extracellular glutamate levels were observed in the NAc. These results indicate that Shati/Nat8l overexpression in the mPFC attenuates METH‐induced CPP by decreasing extracellular DA in the NAc. In contrast, Shati/Nat8l‐mPFC overexpression did not alter METH‐induced hyperlocomotion. This study demonstrates that Shati/Nat8l in the mPFC attenuates METH reward‐seeking behaviour but not the psychomotor activity of METH.