Regulation of prolactin in mice with altered hypothalamic melanocortin activity

This study used two mouse models with genetic manipulation of the melanocortin system to investigate prolactin regulation. Mice with overexpression of the melanocortin receptor (MC-R) agonist, α-melanocyte- stimulating hormone (Tg-MSH) or deletion of the MC-R antagonist agouti-related protein (AgRP KO) were studied. Male Tg-MSH mice had lower blood prolactin levels at baseline (2.9 ± 0.3 vs. 4.7 ± 0.7 ng/ml) and after restraint stress (68 ± 6.5 vs. 117 ± 22 ng/ml) vs. WT (p < 0.05); however, pituitary prolactin content was not different. Blood prolactin was also decreased in male AgRP KO mice at baseline (4.2 ± 0.5 vs. 7.6 ± 1.3 ng/ml) and after stress (60 ± 4.5 vs. 86.1 ± 5.7 ng/ml) vs. WT (p < 0.001). Pituitary prolactin content was lower in male AgRP KO mice (4.3 ± 0.3 vs. 6.7 ± 0.5 μg/pituitary, p < 0.001) vs. WT. No differences in blood or pituitary prolactin levels were observed in female AgRP KO mice vs. WT. Hypothalamic dopamine activity was assessed as the potential mechanism responsible for changes in prolactin levels. Hypothalamic tyrosine hydroxylase mRNA was measured in both genetic models vs. WT mice and hypothalamic dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) content were measured in male AgRP KO and WT mice but neither were significantly different. However, these results do not preclude changes in dopamine activity as dopamine turnover was not directly investigated. This is the first study to show that baseline and stress-induced prolactin release and pituitary prolactin content are reduced in mice with genetic alterations of the melanocortin system and suggests that changes in hypothalamic melanocortin activity may be reflected in measurements of serum prolactin levels.