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Serotonin (5-HT), a neurotransmitter synthesized from tryptophan, has been proposed as a feedback inhibitor of lactation. We determined that the gene coding for tryptophan hydroxylase 1, the rate-limiting enzyme for 5-HT synthesis, is expressed in bovine mammary epithelial cells in vitro and is upregulated by prolactin. In addition, 5-HT reduced the expression of α-lactalbumin and casein genes in vitro. Furthermore, inhibiting 5-HT synthesis with p-chlorophenylalanine or blocking the 5-HT receptor with methysergide (METH) increased milk protein gene expression. We then evaluated effects of intramammary 5-HT or METH infusion on production and milk composition in 6 multiparous Holstein cows. Cows were assigned to a repeated measures design of contralateral intramammary infusions of METH (20 mg/quarter per d) or saline for 3 d followed by a 7-d washout period before administering 5-HT (50 mg/quarter/d) or SAL for 3 d. For each udder half, milk yield was recorded twice and composition was determined once per day. Blood samples were harvested each day for plasma to determine glucose and nonesterified fatty acid concentrations. Evaporative heat loss, respiration rate, left and right udder temperatures, and rectal temperatures were obtained after each milking to evaluate possible systemic effects of infusions. During METH and saline infusions milk yield increased 10.9%. During 5-HT and saline infusion milk yield decreased 11.1%. Milk yield and physiological responses suggested intramammary 5-HT and METH doses were high enough to cause systemic effects. Infusing saline, METH, and 5-HT increased milk SCC. Infusing 5-HT tended to reduce mean lactose concentration (4.3 vs. 4.6%) relative to saline. Milk protein content was decreased by METH and SAL (2.0%) and was increased (5.8%) by 5-HT followed by a 33% decrease postinfusion. Infusion of METH increased evaporative heat loss 11%, which decreased 11% postinfusion. Infusions of 5-HT or METH did not affect plasma nonesterified fatty acid or glucose concentrations, respiration rate, or milk fat content. We conclude 5-HT infusion reduced milk synthesis, whereas blocking the 5-HT receptor with METH increased milk synthesis. Doses of 5-HT and METH used in this study likely resulted in systemic effects. These data support the concept that 5-HT is a feedback inhibitor of lactation in the bovine.