Suppression of lactation and acceleration of involution in the bovine mammary gland by a selective serotonin reuptake inhibitor

Serotonin (5-HT) is a homeostatic regulator of lactation. Selective 5-HT reuptake inhibitors (SSRI) are commonly prescribed pharmaceuticals that inhibit activity of the 5-HT reuptake transporter, increasing cellular exposure to 5-HT. Use of SSRIs has been shown to alter lactation performance in humans and 5-HT has been shown to reduce milk yield in cattle. However, it has not been determined how SSRI treatments affect the bovine mammary gland. We evaluated the effects of SSRI (fluoxetine (FLX)) administration on tight junctions (TJs) and milk protein gene expression in a lactogenic culture model, using primary bovine mammary epithelial cells (pBMEC). Additionally, we evaluated the effects of intramammary infusions of FLX and 5-hydroxytryptophan on milk production and TJ status in multiparous Holstein cows at dry-off. Treatment of pBMEC cultured on permeable membranes disrupted TJs, as measured by transepithelial resistance and immunostaining for zona occludens 1. Correspondingly, treatment of '3D', collagenembedded lactogenic cultures of pBMEC with FLX suppressed milk protein gene expression (α-lactalbumin and β-casein) in a concentration-dependent manner. Finally, intramammary treatment of Holstein cows with FLX resulted in an accelerated rate of milk decline. Additionally, TJ permeability increased in FLX-treated animals, as measured by plasma lactose and milk Na⁺ and K⁺ levels. Results of these experiments imply that SSRI administration accelerates the rate of mammary gland involution through disassembly of TJs and inhibition of milk protein gene expression in vitro and in vivo, leading to reduction of milk yield.