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Serotonin Transport and Metabolism in the Mammary Gland Modulates Secretory Activation and Involution

Department of Molecular and Cellular Physiology (A.M.M., L.L.H., N.D.H.), and Systems Biology and Physiology Program (A.M.M., K.A.G., N.D.H.), University of Cincinnati, Cincinnati, Ohio 45267-0576; Division of Neonatology (L.A.N.-R.), Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229; Department of Nutrition (K.G.D.), University of California at Davis, Davis, California 95616-8669; Department of Pediatrics (C.J.C.), University of California Davis Medical Center, Sacramento, California 95817; and James L. Winkle College of Pharmacy (K.A.G.), University of Cincinnati, Cincinnati, Ohio 45267

Address all correspondence and requests for reprints to: Nelson D. Horseman, 231 Albert Sabin Way, Molecular and Cellular Physiology, Cincinnati, Ohio 45267-0576. E-mail: nelson.horseman{at}uc.edu.

Context: Serotonin [5-hydroxytryptamine (5-HT)] is an important local regulator of lactation homeostasis; however, the roles for the serotonin reuptake transporter and monoamine oxidase have not been known.

Objective: The aim of the study was to determine whether drugs that impact 5-HT affect human lactation physiology.

Design and Setting: We conducted laboratory studies of human and animal models and an observational study of the onset of copious milk secretion in postpartum women at a university medical center.

Participants: We studied women expecting their first live-born infant; exclusion criteria were: referred to the medical center for another medical condition, known contraindication to breastfeed, and less than 19 yr of age and unable to obtain parental consent.

Intervention(s): The mothers were interviewed. The cell and animal studies consisted of a variety of biochemical, pharmacological, and genetic interventions.

Main Outcome Measure(s): The human subjects outcome was prevalence of delayed onset of copious milk secretion. The cell and animal outcomes were physiological and morphological.

Results: Inhibiting serotonin reuptake in mammary epithelial cells altered barrier function, and the effects were amplified by coadministering a monoamine oxidase inhibitor. Direct delivery of fluoxetine by slow-release pellets caused localized involution. TPH1 knockout mice displayed precocious secretory activation. Among a cohort of 431 women, those taking SSRI were more likely (P = 0.02) to experience delayed secretory activation.

Conclusions: 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.