Histamine system is suggested to have a role in mammary gland growth regulation, differentiation and functioning during pregnancy and lactation. Histidine decarboxylase activity undergoes significant changes during pregnancy and lactation. Pregnancy associated elevation of HDC activity and mRNA transcript in mouse mammary gland was successfully affected by enzyme antisense oligonucleotides treatment. The enzyme activity of resting mammae was unaffected as it lacked inducible pool of HDC. The short-term mammary histamine shortage evoked influenced the mRNA expression of histamine receptors (H1 and H2) and ornithine decarboxylase during pregnancy. There were essentially no morphological changes in the mammary gland upon the treatment, however, adipocytes neighbouring alveolar structures were more pronounced. These findings further substantiate the role of histamine in mammary gland physiology and emphasise presence of common motifs of biogenic amines and polyamine metabolism as well as mutual interferences implicating observed “cross-talk” phenomenon.