1. Nicotinamide phosphoribosyltransferase regulates cocaine reward through Sirtuin 1
- Author
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Li Luo, Linhong Jiang, Baolai Zhang, Dengqi Fu, Yinglan Zhao, Yan Li, Hailei Long, Jueying Kong, Hui Gu, Xiaobo Cen, Wei Jiang, Qian Zhao, Ruiming Zhu, Xue Shao, Pengchi Deng, and Changman Du
- Subjects
0301 basic medicine ,Magnetic Resonance Spectroscopy ,Nicotinamide phosphoribosyltransferase ,Mice, Transgenic ,Nicotinamide adenine dinucleotide ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Developmental Neuroscience ,Cocaine ,Dopamine Uptake Inhibitors ,Reward ,Sirtuin 1 ,Mesencephalon ,Conditioning, Psychological ,medicine ,Animals ,Nicotinamide Phosphoribosyltransferase ,Nicotinamide mononucleotide ,biology ,Nicotinamide ,Ventral Tegmental Area ,Cell biology ,Ventral tegmental area ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,chemistry ,biology.protein ,Cytokines ,NAD+ kinase ,Histone deacetylase ,030217 neurology & neurosurgery ,Locomotion - Abstract
Nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis in mammals, converts nicotinamide into nicotinamide mononucleotide (NMN). NMN is subsequently converted to NAD, a component that is critical for cell energy metabolism and survival. Sirtuin 1 (SIRT1), an NAD-dependent histone deacetylase, plays an important role in mediating memory and synaptic plasticity. Here, we found that NAMPT was significantly upregulated in the ventral tegmental area (VTA) of cocaine-conditioned mice. Intraperitoneal or intra-VTA injection of FK866, a specific inhibitor of NAMPT, significantly attenuated cocaine reward. However, such effects were clearly repressed by intra-VTA expression of NAMPT or supplementation with NMN. Using 1H-nuclear magnetic resonance metabolomic analysis, we found that the content of NAD and NMN were increased in the VTA of cocaine-conditioned mice; moreover, the expression of SIRT1 was also upregulated. Interestingly, the inhibitory effect of FK866 on cocaine reward was significantly weakened in Sirt1 midbrain conditional knockout mice. Our results suggest that NAMPT-mediated NAD biosynthesis may modify cocaine behavioral effects through SIRT1. Moreover, our findings reveal that the interplay between NAD biosynthesis and SIRT1 regulation may comprise a novel regulatory pathway that responds to chronic cocaine stimuli.
- Published
- 2017