Inhibitory effects of Shati/Nat8l overexpression in the medial prefrontal cortex on the methamphetamine induced-CPP in mice

[Speaker] Meriem Haddar:1
[Co-author] Kyosuke Uno:1, Shin-Ichi Muramatsu:2,3, Atsumi Nitta:1
1:Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, Graduate School of Medecine and Pharmaceutical Sciences for Education, University of Toyama, Toyama, Japan, 2:Division of Neurology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan, 3:Center for Gene & Cell Therapy, Institute of Medical Science, The University of Tokyo, Japan

[Background] Shati/Nat8l is a novel N-acetyltransferase which generates N-acetylaspartate from aspartate and acetyl-CoA. It has been identified from the nucleus accumbens (NAc) of mice treated with methamphetamine (METH). Shati/Nat8l overexpression in the NAc attenuates METH action. Shati/Nat8l mRNA levels were higher in the prefrontal cortex (PFC) compared to other brain regions. In another hand, several human psychiatric conditions, including substance abuse, have been linked to altered medial PFC (mPFC) function. Indeed, it is reported that after METH self-administration and during reinstatement, dopamine (DA) and glutamate dysregulation were observed in PFC and nucleus accumbens of rats. METH abuse may alter DA receptive pyramidal neurons in the PFC, in turn affecting downstream signaling in the nucleus accumbens. However, the mechanism underlying mPFC control over reward system and the function of Shati/Nat8l in mPFC have not been clarified. In this research we try to understand the function of mPFC Shati/Nat8l in methamphetamine addiction.

[Methods] We generated Shati/Nat8l mPFC overexpressed mice using AAV vector and GFP mice (control) and checked the overexpression by qRT-PCR. After 3 weeks we performed conditioned place preference (CPP) and locomotor activity (LA) after saline or METH treatment. Next, we performed immunohistochemistry using GFP antibody to confirm the connection of mPFC to reward system.

[Results] Shati/Nat8l mRNA levels were significantly increased in mPFC of mice injected with AAV vector containing Shati/Nat8l, and interestingly showed attenuation in methamphetamine response during CPP experiment, however, Shati/Nat8l overexpressed mice didn't affect methamphetamine-induced locomotor activity. Meanwhile, immunohistochemistry of mice injected with GFP in mPFC showed green fluorescence in different brain regions mainly in NAc and STR, which explain a clear projection of mPFC neurons into the NAc and striatum (STR).

[Discussion and Conclusion] The attenuation of methamphetamine response observed in CPP could be mediated by specific projecting neurons from mPFC to NAc MSN neurons, which might reduce DA release in the NAc.
From these experiments we can conclude that Shati/Nat8l overexpression in mPFC attenuates methamphetamine response in CPP but not in locomotor activity.

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