Bile formation is regulated by hormones, regulatory peptides, and neurotransmitters. Histamine is a biogenic amine that is mainly produced in mast cell, basophile, and neuron. The histaminergic neurons are located in the tuberal region of the posterior hypothalamus in the tuberomammillary nucleus which contains five nucleuses. The E2 nucleus is larger, its activity is more than the other nucleuses, and it also has 50 % of all histaminergic neurons. The aim of the present work was to establish the role of histamine injected into the E2 nucleus in the central regulation of bile secretion, serum lipids level, and hepatic enzymes in the rat. Rats were cannulated in the E2 nucleus for the administration of 1 μl histamine. After 1 week, the common bile duct was cannulated and bile samples were collected every 15 min for 60 min after the administration of histamine, and biochemical analyses were done on blood samples. Centrally applied histamine increased bile secretion at all studied periods, indirect bilirubin, total bilirubin, and low-density lipoprotein cholesterol levels. The results showed that histamine participates in the central regulation of bile secretion in the rat, and the E2 nucleus can be a special site for the regulation of bile secretion and lipid levels. These findings give further insight into the complexity of brain–liver interaction.