J Mammary Gland Biol Neoplasia (2014) 19:139–146 DOI 10.1007/s10911-013-9304-6

Serotonin and Serotonin Transport in the Regulation of Lactation Aaron M. Marshall & Laura L. Hernandez & Nelson D. Horseman

Received: 3 September 2013 / Accepted: 7 October 2013 / Published online: 18 October 2013 # Springer Science+Business Media New York 2013

Abstract Serotonin (5-HT), classically known as a neurotransmitter involved in regulating sleep, appetite, memory, sexual behavior, neuroendocrine function and mood is also synthesized in epithelial cells located in many organs throughout the body, including the mammary gland. The function of epithelial 5-HT is dependent on the expression of the 5-HT receptors in a particular system. The conventional components of a classic 5-HT system are found within the mammary gland; synthetic enzymes (tryptophan hydroxylase I, aromatic amino acid decarboxylase), several 5-HT receptors and the 5HT reuptake transporter (SERT). In the mammary gland, two actions of 5-HT through two different 5-HT receptor subtypes have been described: negative feedback on milk synthesis and secretion, and stimulation of parathyroid hormone relatedprotein, a calcium-mobilizing hormone. As with neuronal systems, the regulation of 5-HT activity is multifactorial, but one seminal component is reuptake of 5-HT from the extracellular space following its release. Importantly, the wide availability of selective 5-HT reuptake inhibitors (SSRI) allows the manipulation of 5-HT activity in a biological system. Here, we review the role of 5-HT in mammary gland function, review the biochemistry, genetics and physiology of SERT, and discuss how SERT is vital to the function of the mammary gland. A. M. Marshall Department of Medical Education, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0576, USA L. L. Hernandez Department of Dairy Science, University of Wisconsin, 1675 Observatory Drive, Madison, WI 53706-1205, USA N. D. Horseman (*) Department of Molecular and Cellular Physiology, Program in Systems Biology and Physiology, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0576, USA e-mail: [email protected]

Keywords Epithelium . Involution . PTHrP . SSRI . Tight junctions Abbreviations 5-HT SERT SSRI 5-HTP TPH AADC MAO 5-HIAA RANKL PTHrP VMAT

serotonin serotonin transporter selective serotonin reuptake inhibitor 5-hydroxy-L-tryptophan tryptophan hydroxylase aromatic amine decarboxylase monoamine oxidase 5-hydroxyindole acetic acid receptor activator of NF-κB ligand parathyroid hormone related protein vesicular monoamine transporters

Biochemistry of Serotonin Serotonin (5-Hydroxytryptamine, 5-HT) is a monoamine synthesized from the essential amino acid L-tryptophan in a twostep reaction. Tryptophan is hydroxylated to 5-hydroxy-L tryptophan (5-HTP) by the enzyme tryptophan hydroxylase (TPH). Oxygen and tetrahydrobiopterin are required cofactors for this first step. TPH is the rate limiting step, and the enzyme occurs as two isoforms in vertebrate species, transcribed from separate genes (TPH1 and TPH2) [1, 2]. TPH2 is localized to neurons, and synthesizes 5-HT used in neurotransmission. TPH1 is expressed peripherally, including the mammary gland of mice, humans and bovine [3, 4]. 5-HT synthesized in the gut is thought to contribute the bulk of 5-HT that circulates in blood. However, studies determining the contribution of the mammary gland to the circulating pool of 5-HT, especially during pregnancy and lactation, have not been published.

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In the next enzymatic step, 5-HTP is decarboxylated by aromatic amine decarboxylase (AADC) to yield 5-HT. Necessary cofactors for this step are vitamin B6, vitamin B3, and magnesium [5]. In the pineal gland and retina, another pair of enzymes, serotonin-N-acetyltransferase; (SNAT) and hydoxyindole-O-methyltransferase, convert 5-HT into melatonin. Reverse transcriptase PCR determined that SNAT was not expressed in the mammary gland of mice [3]. 5-HT is catabolized to an inactive form (5-hydroxyindole acetylaldehyde) by the ubiquitous enzyme monoamine oxidase (MAO). 5hydroxyindole acetylaldehyde is acted upon by aldehyde dehydrogenase to yield 5-hydroxyindole acetic acid (5-HIAA). 5-HIAA circulates in plasma, is excreted in the urine, and thus used as an indicator of whole body 5-HT turnover [6]. Although TPH1 and TPH2 are compartmentalized in terms of their expression, 5-HTP is able to freely cross the blood-brain barrier, while 5-HT cannot [7]. In addition, amino acid transporters carry L-tryptophan across the blood-brain barrier; however tryptophan must compete with other large neutral, and branched-chain amino acids for a common transporter [8].

5-HT and Lactation Homeostasis 5-HT has a primary functional role in several physiological systems, and subsidiary roles in many more. The wellaccepted roles of 5-HT are neurotransmission, hemostasis, gut motility and secretion, and the cardiovascular system, which have been extensively reviewed elsewhere [9–11]. The range of 5-HT functions within one organ or across an organism is attributable the diversity of 5-HT receptors: seven families (5-HT1-7) transcribed from (depending on the species) ~13 separate genes [12, 13]. Most 5-HT receptors are G-protein coupled, the exception being the 5-HT3 family, which are ligand-gated cation channels. Members of the 5-HT1 and 5-HT5 classes are Gi/o coupled; 5-HT2 family is Gq/11, and 5-HT4, 5-HT6 and 5-HT7 are Gs coupled. Further adding to the diversity, some 5-HT receptor genes, such as 5-HT2C and 5-HT7, yield multiple isoforms from differential splicing events [13]. Main differences between isoforms within one family are their relative distribution, structure and sensitivity to various agonists and antagonists. 5-HT in the mammary gland has an important physiological role by controlling alveolar volume homeostasis [3, 4, 14, 15], acting in an autocrine/paracrine fashion to trigger the beginning stages of involution. Many events mark the beginning of involution, but an important early event is increased tight junction permeability [16]. During lactation, tight junctions maintain an important barrier, separating the milk space from the interstitial fluid. The breakdown of these tight junctions and presence of milk components in the interstitium signals the beginning of involution. Since tight junctions are an important component of this response, 5-HT was

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investigated as an autocrine/paracrine mediator of tight junction permeability utilizing a polarized, high-resistance barrier, mammary epithelial cell model [14]. A biphasic effect of 5-HT is observed in the mammary epithelium [17]. 5-HT initially causes a transient decrease in tight junction permeability, followed by a precipitous increase in permeability. The transient effect may support lactation by sustaining the status quo between nursing bouts, while the latter presumably facilitates the transition from lactation to involution. Each response occurs downstream of the 5-HT7 receptor; however the increased tight junction resistance is mediated by cAMPdependent PKA, and the opening of the tight junctions is through a cAMP-dependent p38 MAP kinase pathway [17]. Other changes that depend on sustained 5-HT signaling are the transition from an active columnar cell shape to the inactive squamous morphology, cell shedding, cell death, and loss of membrane polarity [18]. Some of these changes appear to be direct effects of 5-HT, but others presumably depend on secondary mediators. The homeostatic actions of 5-HT in the mammary epithelium are related to actions in other fluid-filled epithelial organs such as the prostate gland, pancreas, and fetal lung. This shared function has been reviewed elsewhere [19].

5-HT and Induction of PTHrP More recently, 5-HT has been shown to act in an autocrine/ paracrine fashion to cause the synthesis and secretion of the calcium-mobilizing hormone, PTHrP [20, 21]. PTHrP has been established as an endocrine factor synthesized during lactation within the mammary gland, which is responsible for mobilization of calcium from bone in order to support milk synthesis (19). Recently, using mice genetically deficient for TPH1 (TPH1-KO), it was determined that PTHrP was undetectable in the circulation and mammary tissue on day 10 of lactation (14). Administration of 5-HTP to TPH1-KO mice, which bypasses the missing enzyme, resulted in prompt induction of PTHrP in both the circulation and the mammary gland. Furthermore, regulation of PTHrP by 5-HT was determined to be through the 5-HT2B receptor subtype. This was supported by induction of PTHrP in mammary epithelial cells by treatment with a selective agonist of the 5-HT2B receptor, and conversely a reduction in PTHrP expression through treatment with a selective 5-HT 2B receptor antagonist [20]. Additionally, the PTHrP response in the mammary gland is not regulated through signaling via the 5-HT7 receptor, which was known to regulate tight junctions [20]. Secretion of PTHrP from the mammary glands during lactation has long been known to serve the function of mobilizing calcium from bone tissue for the synthesis of milk [22]. Specifically, PTHrP acts on osteoblast cells in the bone to induce RANKL, which is critical to the maturation of

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osteoclasts, the cells responsible for bone breakdown [23]. Administration of 5-HTP to rats during the late pregnancy/ early lactation period resulted in increased PTHrP in the mammary gland and the circulation, further confirming a role for 5-HT to stimulate mammary synthesis of PTHrP [24]. Bone resorption was increased by feeding 5-HTP, as shown by increased numbers and size of osteoclasts, as well as increased expression of cathepsin K, RANKL and TRAP [23]. Circulating 5-HT concentrations were positively correlated with PTHrP concentrations and negatively correlated with incidence of milk fever in dairy cattle [21]. Clinical and subclinical hypocalcemia occur more frequently in dairy cattle than other mammals because of the sudden and high demand for calcium [25]. Prior to determining a role for 5-HT in regulating PTHrP, little was known about the factors regulating PTHrP synthesis and secretion in the mammary gland. The biological actions ascribed to 5-HT in the mammary glands thus far are summarized in Fig. 1. The 5-HT receptors involved, such as 5-HT2B and 5-HT7 noted here, differ in various properties such as affinities, localization, desensitization, and signal transduction. These differences, combined with the dynamic nature of 5-HT synthesis and secretion, enable the mammary epithelium to interpret changes in the local environment. The following sections summarize important aspects of these components, focusing primarily on metabolism and transport mechanisms.

Fig. 1 Biological activities of 5-HT in the mammary glands. Suckling leads to synthesis and secretion of milk into the alveoli. As a consequence, calcium is transported from the blood into milk, decreasing blood calcium levels. 5-HT, acting via 5HT2B, induces PTHrP secretion from the mammary epithelium, which induces bone mobilization (increase blood calcium). Acting via 5-HT7 receptors, aspects of mammary epithelial homeostasis are regulated by 5-HT. If milk letdown does not occur, leading to milk stasis, sustained elevation of 5-HT activates alternative 5HT7 transduction mechanisms (p38), which initiates the earliest events associated with involution (opening tight junctions, squamous transition, cell shedding, etc.)

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Metabolism of 5-HT The regulation of 5-HT action is a balance between several competing kinetic systems. The key players can be generically classified as metabolic regulators (synthetic and degradative enzymes), regulators of transport (vesicular and plasma membrane) and the 5-HT receptors themselves. The mammary gland has been found to contain all these components [14, 15]. Here, we review the metabolic regulatory components. TPH, the rate limiting enzyme in the biosynthesis of 5-HT, is a member of the aromatic amino acid hydroxylases (AAAH), which includes tyrosine hydroxylase, phenylalanine hydroxylase, TPH1 and TPH2 in vertebrate species, and related enzymes in other taxa. All members have an aminoterminal regulatory domain (R-domain), a central catalytic domain and a carboxy-terminal tetramerization domain. The carboxy-terminus of tyrosine hydroxylase contains a leucine zipper (427-444aa) that when mutated results in dimers that are inactive [26]. In contrast, although deletion of the leucine zipper in TPH resulted in dimers and monomers only, activity was indistinguishable from the tetramer [27]. This has led to the hypothesis that tetramerization of TPH serves a regulatory, rather than catalytic, role. The mammary gland exclusively expresses TPH1, whereas TPH2 is distributed in neuronal tissue. TPH2 differs from TPH1 at its N-terminus (R-domain), containing 41 additional amino acids including an additional phosphorylation site. Phosphorylation of TPH2 at this additional site (serine 19), has been shown to facilitate interaction with the 14-3-3 protein, increasing TPH2 stability [28]. By implication, it could be inferred that TPH1 is relatively less stable, and indeed that prediction has been borne out [29, 30]. The discovery of the second isoform of TPH occurred in 2003, and thus data published prior to that are confounded by the unknown identification of TPH isoforms. The discovery of TPH1 and the 5-HT system in the mammary gland was the result of comparing messenger RNA transcripts of non-secretory mammary glands (prolactin knockout mice) versus hypersecretory mammary glands (hyperprolactinemic mice). TPH1 was highly induced in the hyperprolactinemic mice [3]. This same study revealed that TPH1 gene expression (and 5-HT synthesis) was induced by fluid stasis and not by prolactin signaling, per se. Monoamine oxidase is a ubiquitously expressed flavoenzyme, found on the outer membrane of mitochondria. There are two isoforms (MAOA & MAOB), originating from separate genes, each on the X-chromosome. Mammary epithelial cells express mRNA transcripts of both isoforms (unpublished data). Both possess an FAD cofactor covalently linked to a cysteine residue. MAOA and B share approximately 70 % sequence homology, however they have drastically different substrate and inhibitor specificities. MAOA degrades norepinephrine, dopamine and is the only MAO able to degrade 5-HT

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[31]. MAOB degrades phenylethylamine and benzylamine; it is also able to degrade dopamine, but with lower efficiency than MAOA [32, 33]. MAOA and B knockout mice have both been created. As expected MAOA −/− mice have elevated levels of 5-HT, dopamine and norepinephrine, resulting in aggressive behavior [34]. MAOB knockout animals do not display aggressive behavior, but do have phenylethylamine accumulation in multiple organs [35]. Neither report on MAOA or B knockout mice reported on lactation-related phenotypes.

Transport of 5-HT All monoamines, including 5-HT, are released into extracellular spaces in large quantities, and often act within a microenvironment. Thus, the concentration of those chemicals in the microenvironment is much higher than in circulation (e.g., four orders of magnitude in synaptic cleft). Therefore, to effectively terminate the signal, plasma membrane monoamine transporters remove monoamine from the extracellular space, and in the case of 5-HT this is performed by the serotonin transporter (SERT). There are two consequences of SERT action: (1) terminating receptor signaling by removing the ligand from the extracellular space, and (2) mediating the accumulation or reaccumulation of 5-HT intracellularly. Reaccumulation occurs in cell types that also have de novo 5-HT synthetic capability (e.g., neurons and mammary epithelia), while accumulation occurs in cell types without synthetic capability (e.g., platelets). By mediating 5-HT accumulation, SERT allows platelets to transport 5-HT throughout the body, despite their lack of a 5-HT synthetic pathway. The plasma membrane transport of 5-HT requires energy, which is obtained by coupling the flow of monoamines to that of sodium. The ubiquitously expressed Na+/K+ ATPase generates an inwardly directed electrochemical sodium gradient utilized by SERT to drive uphill transport of 5-HT. Although research is still uncovering the mechanism of transport and its stoichiometry, the current dogma is Na+, Cl- and 5-HT bind and cause a conformational change, resulting in transport into the cell. Potassium then binds and is transported out, setting the transporter back to its original conformation. The overall stoichiometry is a 1:1:1:1 electroneutral exchange of K+ with Na+, Cl- and 5-HT+ [36–38]. Until recently, the structure-function relationships of SERT and other neurotransmitter transporters were the subject of speculation, due to lack of a suitable model. A tryptophan transporter, with properties similar to neurotransmitter transporters, was newly crystallized [39]. This has spurred the process of identifying binding sites and extrapolating altered function from site-directed mutagenesis [40]. One recently explored area of research with regard to SERT is its trafficking into and out of the membrane. The C-terminal end of the peptide is essential for its trafficking, as a 15 amino acid deletion completely abolished membrane bound SERT [41]. Interestingly, it was recently shown that 5-HT is

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covalently attached to Rab4, which locks it in its GTP bound form. GTP-bound Rab4, then binds to the C-terminus of SERT and locks the protein intracellularly, thereby “paralyzing” it [42]. In addition, a study using a recombinant baculovirus system suggested N-linked glycosylation was important for membrane localization of SERT. Other proteins have been identified as affecting SERT distribution into and out of the membrane, such as PKC, PKG, t -SNARE and SCAMP2 [43–45]. PKC decreases the abundance of SERT in the membrane, therefore decreasing 5-HT uptake, while PKG does the opposite [43–45]. In the mammary epithelium, SERT is exclusively localized to the apical membrane, however, within the heterogeneous mammary tissue, SERT expression is also found in stromal cells immediately adjacent to the basement membrane [15]. The localization of SERT in the apical membrane presumably reabsorbs 5-HT from the milk, which may be secreted apically, or leak from the basolateral compartment, depending on the tight junction status (Fig. 2). The genetics of SERT has also gained prominence in published literature in the last decade. This is due to genetic variants of SERT being associated with psychiatric disorders, including autism and obsessive-compulsive disorder. Of particular interest are variants that directly or indirectly affect the phosphorylation status of SERT. Phosphorylation of SERT is downstream of PKG, but SERT is not directly a PKG substrate [46]. Activation of PKG and subsequent phosphorylation of SERT was observed downstream of nitric oxide signaling and adenosine receptor activation, and results in increased activity of SERT. Studies regarding genetic variants of SERT and mammary gland development/lactation have not been performed. Vesicular monoamine transporters (VMAT) are fairly nonspecific transporters whose function is to compartmentalize monoamines in secretory vesicles. They belong to the vesicular amine transport (VAT) family (SLC18). In the nervous system, the vesicles are derived from the endosomal compartment, while in endocrine cells secretory granules originate from the Golgi. Regardless of their origin, the mechanism of monoamine uptake is an active transport process. VMAT is an antiporter, exchanging H+, for a monoamine. The driving force is a concentration gradient of H+ generated by the vacuolar H+-ATPase, located on the same vesicles. There have been two isoforms of human VMAT cloned (VMAT1 and VMAT2) [47, 48]. VMAT2 is the predominant isoform expressed in nervous tissue, and in the neuroendocrine cells of the stomach. VMAT1 is expressed in the neuroendocrine cells of the small intestine and mammary epithelial cells (unpublished data). Both isoforms are coexpressed in the adrenal medulla. Substrate specificity is largely similar between the two isoforms, especially with respect to 5-HT and dopamine transport [49]. VMAT1 is capable of transporting norepinephrine and histamine more efficiently (4 and 33 fold, respectively). The two isoforms are also differentially sensitive to pharmacologic agents such as amphetamines, MDMA

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Fig. 2 Schematic showing the component parts of the serotonin (5-HT) system in the mammary epithelium. The diagram illustrates the presence of the tryptophan hydroxylase 1 (TPH1) and aromatic amine decarboxylase (AADC), vesicular monoamine transporter (VMAT), serotonin transporter (SERT) and serotonin receptors type 7 (5HT7). Serotonin transporter (SERT) in the apical epithelial membrane, and in adjacent stromal cells. Bi-directional secretion of 5HT is illustrated. Larger vesicles of 5-HT at the basal membranes designate the dominant direction of secretion

and fenfluramine; in every case VMAT2 being more sensitive [49, 50]. One question yet to be definitively answered about mammary gland secretion of 5-HT is the direction of secretion: being apical, basolateral, or both. Quantitative methods for determining 5-HT concentration in different fluid compartments have been undertaken, but are complicated by the labile nature of 5-HT. Distribution of the 5-HT7 receptor is basolateral, implying basolateral secretion of 5-HT. Moreover, other epithelial systems that have 5-HT secreting cells (such as the gut) have basally located 5-HT secretory vesicles [51]. SERT is located apically in the mammary epithelium and also in stromal cells of the lactating mammary tissue [15]. Taken altogether, we speculate that 5-HT is primarily released basally, but may also be released apically as an incidental consequence of milk secretion (Fig. 2). Apically expressed SERT would serve as a conservation and recycling mechanism for 5HT that is released apically. Definitive immunogold electron microscopy studies should be performed on lactating mammary tissue in order to decisively determine the location and direction of secretion of 5-HT containing vesicles.

Selective Serotonin Reuptake Inhibitors and Lactation The discovery of the 5-HT system and its regulatory components in the functioning mammary gland, immediately led to questions about the effects (positive and negative) of pharmacologic agents affecting serotonin activity. One of the most prescribed classes of drugs is the selective serotonin reuptake

inhibitors (SSRI). SSRIs act by blocking the reuptake of 5-HT into the cell and thus increase the amount of 5-HT in the local milieu [52]. Several lines of investigation have been explored to begin to elucidate the consequence of SSRI exposure during lactation. Utilizing a human mammary epithelial cell line, it was shown that the reference drug for this class, fluoxetine, had a similar response profile to 5-HT itself [15]. Specifically, cells were cultured on permeable supports that allowed the

Fig. 3 5-HT activity regulating epithelial homeostasis. Over time (x-axis) the mammary alveolar spaces fill (milk stasis time). Concomitantly, 5-HT activity increases (y-axis). At some threshold, determined by signal transduction via 5-HT7 receptors, TJ opening occurs locally (indicated by dashed line). If this local effect is widespread throughout the epithelium of the gland, it will initiate early involution processes. The presence of an SSRI results in a leftward shift of the curve, leading to a more rapid and widespread transition to TJ opening, and early involution

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polarization of an in vitro epithelium and formation of high resistance tight junctions [53]. Fluoxetine, similar to 5-HT, caused a biphasic response in the permeability of the epithelium. At lower concentrations and earlier time points, fluoxetine decreased the permeability of the epithelium; while at higher concentrations and later time points increased permeability was observed. Increasing permeability is a hallmark of the beginning of involution [54]. Plasma lactose, not normally present during active lactation, can be assayed and serves as another marker for involution. This action of fluoxetine supports the role for 5-HT as homeostatic regulator of milk secretion. Consequently, studies were performed to show that involution can be accelerated in rodents and in dairy cows administered SSRIs [4]. Another line of investigation dealt with answering the question of establishing lactation in the immediate post-partum period. In this case it was hypothesized that enhanced 5-HT activity, caused by the presence of an SSRI, might delay lactogenesis (secretory activation). Indeed, tight junction closure is a requisite step in the formation of a fully functioning, milk-producing mammary gland [54]. To this end, epidemiological evidence was collected from a cohort of women in the peripartum period. Women who were taking an SSRI drug during the third trimester and into the post-partum period were more likely to experience a delay in secretory activation [53]. The average delay was 24 h, and this delay pushed the average time to full lactogenesis beyond the 72 h mark, a point where newborns can begin experiencing substantial weight loss and dehydration if not given supplementary nutrition. This finding was confirmed in a subsequent prospective cohort study in which SSRI use was strongly associated with failure to successfully initiate breastfeeding [55]. Further investigation of this phenomenon is needed. Of particular interest will be use of SSRI to treat post-partum depression, and whether the introduction of an SSRI at that stage affects lactation. SSRIs have been utilized for decades to treat depression and anxiety disorder. Similar to the binding of 5-HT itself, some but not all SSRIs are dependent on ion binding to the transporter. It is still unclear if these drugs bind to the same domain as 5-HT or operate through indirect mechanism(s) [56]. Studies in neuronal systems have complicated the understanding of the molecular pharmacology of SSRIs. In neurons, SSRI treatment initially causes an increase in 5-HT activity at the cell body and this causes changes in the sensitivity and auto-activity of certain 5-HT receptors. Longer term exposure to SSRI eventually causes downregulation of these autoreceptors, leading to disinhibition of 5-HT release at the axon terminal [57, 58]. This complicated response to SSRIs in neuronal systems may be one reason for delayed onset of the therapeutic action of these agents. SSRI effects on involution in the mammary gland are also delayed, but perhaps for a different reason other than receptor autoactivity. Release of 5-HT in the mammary gland is increased by filling of the alveolus, and its distension [3]. In

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Fig. 3, we illustrate how cellular exposure to 5-HT increases during filling of the luminal space, to the level at which it signals opening of tight junctions (via p38 MAPK). Below this threshold, we postulate that the signaling via the PKA pathway predominates, maintaining epithelial tight junction integrity. The figure also illustrates that the presence of an SSRI will cause a leftward shift in the 5-HT activity curve, accelerating the rate at which the gland reaches the threshold for initiating the involution signal (Fig. 3).

Conclusion 5-HT is a multifaceted regulator of lactation and mammary epithelial homeostasis. To date explicit roles have been ascribed to two of the receptor types expressed in the mammary gland. The Gs-coupled 5-HT7 receptors mediate several aspects of epithelial homeostasis, including tight junctions, cell survival, and cell shedding. Gq/11-coupled 5-HT2 type receptors mediate the induction of PTHrP gene expression and secretion, thereby participating in the control of bone mineral mobilization. Future goals will be to understand better the roles of monoamine signaling in mammary gland disease processes, and exploit therapeutic or other interventions targeted to the mammary 5-HT system.

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Serotonin and serotonin transport in the regulation of lactation.

Serotonin (5-HT), classically known as a neurotransmitter involved in regulating sleep, appetite, memory, sexual behavior, neuroendocrine function and...
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