期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：11
DOI：10.1073/pnas.2117113119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
We analyzed the liver metabolome of mice deficient in the expression of the dopamine D2 receptor (D2R) in striatal medium spiny neurons (iMSN-D2RKO) and found profound changes in the liver circadian metabolome compared to control mice. Additionally, we show activation of dopaminergic circuits by acute cocaine administration in iMSN-D2RKO mice reprograms the circadian liver metabolome in response to cocaine. D2R signaling in MSNs is key for striatal output and essential for regulating the first response to the cellular and rewarding effects of cocaine. Our results suggest changes in dopamine signaling in specific striatal neurons evoke major changes in liver physiology. Dysregulation of liver metabolism could contribute to an altered allostatic state and therefore be involved in continued use of drugs.
The circadian clock is tightly intertwined with metabolism and relies heavily on multifaceted interactions between organ systems to maintain proper timing. Genetic and/or environmental causes can disrupt communication between organs and alter rhythmic activities. Substance use leads to altered dopamine signaling followed by reprogramming of circadian gene expression and metabolism in the reward system. However, whether altered dopamine signaling in the brain affects circadian metabolism in peripheral organs has not been fully explored. We show that dopamine D2 receptors (D2R) in striatal medium spiny neurons (MSNs) play a key role in regulating diurnal liver metabolic activities. In addition, drugs that increase dopamine levels, such as cocaine, disrupt circadian metabolic profiles in the liver, which is exacerbated by loss of D2R signaling in MSNs. These results uncover a strict communication between neurons/brain areas and liver metabolism as well as the association between substance use and systemic deficits.
