Hernandez LL, Gregerson KA, Horseman ND. Mammary gland serotonin regulates parathyroid hormone-related protein and other bonerelated signals. Am J Physiol Endocrinol Metab 302: E1009-E1015, 2012. First published February 7, 2012 doi:10.1152/ajpendo.00666.2011.-Breast cells drive bone demineralization during lactation and metastatic cancers. A shared mechanism among these physiological and pathological states is endocrine secretion of parathyroid hormone-related protein (PTHrP), which acts through osteoblasts to stimulate osteoclastic bone demineralization. The regulation of PTHrP has not been accounted for fully by any conventional mammotropic stimuli or tumor growth factors. Serotonin (5-HT) synthesis within breast epithelial cells is induced during lactation and in advancing breast cancer. Here we report that serotonin deficiency (knockout of tryptophan hydroxylase-1) results in a reduction of mammary PTHrP expression during lactation, which is rescued by restoring 5-HT synthesis. 5-HT induced PTHrP expression in lactogen-primed mammary epithelial cells from either mouse or cow. In human breast cancer cells 5-HT induced both PTHrP and the metastasis-associated transcription factor Runx2/Cbfa1. Based on receptor expression and pharmacological evidence, the 5-HT2 receptor type was implicated as being critical for induction of PTHrP and Runx2. These results connect 5-HT synthesis to the induction of bone-regulating factors in the normal mammary gland and in breast cancer cells.5-hydroxytryptamine; lactation; osteoblast; prolactin; RANK ligand; RUNX2/CBFA1 A KEY FUNCTION OF THE MAMMARY GLANDS is to regulate the mobilization of calcium from bone. During lactation women and other mammals lose a significant portion of bone mass, which is restored after lactation ceases (2,8,26,54). Failure to mobilize bone calcium extraction at the onset of lactation causes hypocalcemia in dairy cows, leading to a severe convulsive syndrome referred to as periparturient paresis or "milk fever" (17, 35). To drive calcium mobilization, the mammary glands become endocrine organs and secrete parathyroid hormone-related peptide (PTHrP) into the bloodstream (9,27,46,50,51,53,54). PTHrP was originally discovered as the factor responsible for humoral hypercalcemia of malignancy and is secreted from a variety of advanced soft-tissue cancers (5,8,28,47). The NH 2 -terminal portion of PTHrP is similar to that of parathyroid hormone (PTH) and acts via the type 1 PTH receptors (PTH1R) to induce the receptor activator of NF-B ligand (RANKL) (34).PTHrP is undetectable in the circulation except during lactation, in advanced metastastic disease, or in patients with hyperprolactinemia (5,6,9,24,42,48). Despite obvious correlations with states of elevated prolactin (PRL), PRL did not induce PTHrP in conventional cell cultures of mammary epithelium (29, 52), and our laboratory has done numerous experiments that confirmed that PRL does not induce PTHrP in mammary cells by a direct mechanism (unpublished results).A previous study showed that serotonin (5...

Medications that perturb serotonin balance dysregulate lactation, and the effects are consistent with those predicted by the physiological effects of intramammary 5-HT bioactivity. Mothers taking serotonergic drugs may need additional support to achieve their breastfeeding goals.

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The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence has cast doubt on the effectiveness of SSRIs, these results support their therapeutic use in the treatment of PPD.