Serotonin has many known roles in the body, from signaling in the brain to coordinating intestinal movements. But researchers at the University of Wisconsin are investigating a new use for the compound in dairy cattle – preventing post-calving hypocalcemia.
Subclinical and clinical hypocalcemia – commonly referred to as milk fever – costs the U.S. dairy industry an estimated $900 million annually between treatment and lost milk yield, wrote Laura Hernandez, associate professor with the department of dairy science at the University of Wisconsin, in her proceedings for the 2015 Western Dairy Management Conference.
Early research with mice and in vitro mammary gland cells helped illuminate the role of serotonin in mammalian lactation, Hernandez said.
Mice genetically deficient in peripheral serotonin were injected with 5-HTP, a serotonin precursor. When re-introduced, the 5-HTP increased blood calcium concentrations as well as the abundance of pumps used to transport calcium into the mammary gland.
Hernandez and her colleagues have since identified multiple serotonin receptors within the mammary cells of cattle.
During lactation in cows, mice and humans, serotonin – also known as 5-HT – is secreted when the mammary gland fills with milk, according to an article in the 2014 Annual Review of Animal Biosciences. This compound, in turn, induces the mammary gland to synthesize parathyroid hormone-related peptide (PTHrP).
PTHrP activates osteoclasts, cells that release calcium from bone into the bloodstream to replace the calcium lost in milk.
“Induction of PTHrP through the 5-HT signaling system may explain why dairy cows, in particular, are very susceptible to a hypocalcemic crisis whereas other species are resistant,” wrote authors Nelson Horseman and Robert Collier, professors emeritus at the University of Cincinnati School of Medicine and the University of Arizona College of Agriculture and Life Sciences, respectively.
“A large cisternal udder has been artificially selected in dairy cows to drain the alveolar spaces efficiently. This reservoir must fill before the alveolar spaces can be fully distended.”
Serotonin is derived from the amino acid tryptophan, and 5-HTP is an intermediate step in this process. Unlike tryptophan, 5-HTP cannot be used in any other metabolic pathway, so less is needed for a greater increase in serotonin. In addition, 5-HTP is a widely available natural supplement, Hernandez said.
A study published last year in the Journal of Dairy Science looked into the effects of 5-HTP on calcium dynamics in multiparous pregnant Holstein cows. Ten control cows were given a daily, one-hour intravenous infusion of saline while another group of 10 cows were given saline plus a 1-milligram-per-kilogram dose of 5-HTP beginning 10 days before the expected parturition date until parturition.
None of the cows that received 5-HTP experienced hypocalcemia, while three control cows experienced clinical hypocalcemia with a total blood calcium level of less than 1.4 mmol per liter. Although the blood calcium levels of both groups declined from two days prior to parturition until calving, all of the cows receiving 5-HTP remained above 1.5 mmol per liter while multiple cows in the control group dipped below 1 mmol per liter.
A second Journal of Dairy Science study repeated the findings of the first, with a 14 percent decrease in the blood calcium levels of 5-HTP-treated cows compared to a 28 percent decrease in untreated cows by day one post-calving. The researchers were also able to attribute this benefit directly to increased bone resorption.
The effects of serotonin on the mammary gland and other tissues are very time- and dose-dependent, Hernandez explained. Higher doses cause mammary gland involution and feedback to suppress lactation.
“That’s why the fact that [5-HTP] affects calcium at quite a low dose is really great because then we are not worried about potential negative effects on milk secretion,” she said.
Although mean colostrum yield on day one was more than 2 kilograms less in the treated cows compared to the untreated cows, there was still a sufficient amount for the offspring. The concentration of immunoglobulin G was also unaffected, explained study authors. From day two to day 30 postpartum, no difference in milk yield was observed between the groups.
Cows treated with 5-HTP also had higher levels of serotonin in their colostrum than control cows. Researchers are planning to look into the effects this may have on calves. Serotonin is known to have a role in gut development and immune function, so the effect may actually be positive, Hernandez said.
The normal glucose and insulin patterns during the transition period do not appear to be affected by prepartum 5-HTP infusions at a 1-milligram-per-kilogram-per-day dose.
Serotonin is known to stimulate gut motility, and multiple studies noted an increase in the frequency of defecation and the looseness of stool in 5-HTP-treated cows. However, the authors reported none of the cows had signs of dehydration.
In a 2016 Journal of Endocrinology article, Hernandez and fellow researchers also administered 5-HTP to multiparous pregnant Jersey cattle. Jerseys have a higher calcium concentration in their milk than Holsteins and therefore have a higher incidence of hypocalcemia, Hernandez said.
Jersey cows given 5-HTP hit their lowest blood calcium concentration before calving and then increased, whereas control Jersey cows hit their low one to two days post-calving, much like the treated and untreated Holsteins. Research on this topic has a lot of potential to better understand the biology of this breed, Hernandez said.
Hernandez and fellow researchers will be submitting an article to the Journal of Dairy Science soon investigating the synergistic effect between 5-HTP administration and negative dietary cation-anion difference diets – such as those with anion salts – in increasing post-calving blood calcium concentrations.
Hernandez would also like to see how the level of calcium in the dry cow diet influences this effect.
It is unknown whether 5-HTP is rumen stable. Samples are being analyzed from a study this spring comparing blood calcium concentrations of cows given unencapsulated, 1 milligram per kilogram and 2 milligrams per kilogram daily 5-HTP doses directly into their rumen with cows given 1 milligram per kilogram intravenous doses.
The initial results look promising, Hernandez said, and a second feeding trial will hopefully be conducted to confirm the results with a larger sample size.
Although the serotonin precursor cannot yet be marketed to producers for the prevention of milk fever, Hernandez is optimistic.
“I have had more and more attendance, more positive feedback and people asking me questions about it, so I think we are going in the right direction, which is exciting,” Hernandez said.
“I never thought in a million years it would get to the point that it is even at right now, so that has been pretty rewarding in and of itself.” 
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Holly Drankhan
- Student
- Michigan State University College of Veterinary Medicine
