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.