HMG-CoA synthase 2 drives brain metabolic reprogramming in cocaine exposure
| Autor: | Xiaobo Cen, Hui Gu, Jie Zhang, Yinglan Zhao, Xue Shao, Yunxuan Tang, Pengchi Deng, Hailei Long |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Hydroxymethylglutaryl-CoA Synthase
Male 0301 basic medicine medicine.medical_specialty Ketone Bodies Biology Nucleus Accumbens Cocaine dependence Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Cocaine Brain Nucleus Internal medicine Ketogenesis medicine Animals Homeostasis Glycolysis Pharmacology Glucokinase medicine.disease Up-Regulation Metabolic pathway 030104 developmental biology Endocrinology Ketone bodies Energy Metabolism Energy source 030217 neurology & neurosurgery |
| Zdroj: | Neuropharmacology. 148:377-393 |
| ISSN: | 0028-3908 |
| DOI: | 10.1016/j.neuropharm.2017.10.001 |
| Popis: | The brain is a high energy-consuming organ that typically utilizes glucose as the main energy source for cerebral activity. When glucose becomes scarce under conditions of stress, ketone bodies, such as β-hydroxybutyrate, acetoacetate and acetone, become extremely important. Alterations in brain energy metabolism have been observed in psychostimulant abusers; however, the mode of brain metabolic programming in cocaine dependence remains largely unknown. Here, we profiled the metabolites and metabolic enzymes from brain nucleus accumbens (NAc) of mice exposed to cocaine. We found that cocaine modified energy metabolism and markedly activated ketogenesis pathway in the NAc. The expression of HMG-CoA synthase 2 (HMGCS2), a critical rate-limiting ketogenesis enzyme, was markedly up-regulated. After switching metabolic pathways from ketogenesis to glycolysis through activation of glucokinase, cocaine-evoked metabolic reprogramming regained homeostasis, and the cocaine effect was attenuated. Importantly, both the pharmacological and genetic inhibition of HMGCS2 significantly suppressed cocaine-induced ketogenesis and behavior. In conclusion, cocaine induces a remarkable energy reprogramming in the NAc, which is characterized by HMGCS2-driven ketogenesis. Such effect may facilitate adaptations to cocaine-induced energy stress in the brain. Our findings establish an important link between drug-induced energy reprogramming and cocaine effect, and may have implication in the treatment of cocaine addiction. |
| Databáze: | OpenAIRE |
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