Infusion Of Prolactin Research Articles

Sexually dimorphic effects of prolactin treatment on the onset of puberty and olfactory function in mice

The onset of puberty is associated with the psychophysiological maturation of the adolescent to an adult capable of reproduction when olfactory signals play an important role. This period begins with the secretion of the gonadotropin-releasing hormone (GnRH) from GnRH neurons within the hypothalamus. This is regulated by kisspeptin neurons that express high levels of transmembrane prolactin receptors (PRLR) that bind to and are activated by prolactin (PRL). The elevated levels of serum PRL found during lactation, or caused by chronic PRL infusion, decreases the secretion of gonadotropins and kisspeptin and compromised the estrous cyclicity and the ovulation. In the present work, we aimed to evaluate the effects of either increased or decreased PRL circulating levels within the peripubertal murine brain by administration of PRL or treatment with cabergoline (Cab) respectively. We showed that either treatment delayed the onset of puberty in females, but not in males. This was associated with the augmentation of the PRL receptor (Prlr) mRNA expression in the arcuate nucleus and decreased Kiss1 expression in the anteroventral periventricular zone. Then, during adulthood, we assessed the activation of the mitral and granular cells of the main (MOB) and accessory olfactory bulb (AOB) by cFos immunoreactivity (ir) after the exposure to soiled bedding of the opposite sex. In the MOB, the PRL treatment promoted an increased cFos-ir of the mitral cells of males and females. In the granular cells of male of either treatment an augmented activation was observed. In the AOB, an impaired cFos-ir was observed in PRL and Cab treated females after exposure to male soiled bedding. However, in males, only Cab impaired its activation. No effects were observed in the AOB-mitral cells. In conclusion, our results demonstrate that PRL contributes to pubertal development and maturation of the MOB-AOB during the murine juvenile period in a sex-dependent way.

Gestational dioxin exposure suppresses prolactin-stimulated nursing in lactating dam rats to impair development of postnatal offspring

A number of epidemiological studies have implicated environmental chemicals including dioxins in the induction of negative effects on child development. To clarify the underlying mechanisms, almost all toxicologists have concentrated on effects on the offspring themselves. We examined an alternative hypothesis that gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly-toxic dioxin, targets factors related to maternal childcare to disturb offspring development. Oral administration of TCDD (1 µg/kg) to pregnant rats on gestational day 15 suppressed maternal licking behavior, a nursing behavior, and mammary gland maturation during the lactational stage, as well as the body weight and short-term memory of postnatal offspring. In support of these findings, maternal production of prolactin, a pituitary hormone essential for nursing including milk production, was decreased during the same period. Intracerebroventricular infusion of prolactin to dioxin-exposed dams restored or tended to restore many of the above defects observed both in mothers and offspring. The TCDD-dependent defects in maternal nursing behaviors can be due to a direct action on aryl hydrocarbon receptor (AHR) of lactating dams, because they did not emerge in AHR-knockout dams or control dams with TCDD-exposed offspring. Further examinations revealed that TCDD induces transforming growth factor β1 expression, which suppresses prolactin-producing cell proliferation, in a nursing period-specific manner. In agreement with this, the number of prolactin-positive cells in nursing dams was decreased by TCDD. These results provide novel evidence that gestational dioxin exposure attenuates prolactin-stimulated nursing in lactating dams to impair offspring development, and that immaturity of prolactin-producing cells can contribute to them.

Impaired hypothalamic leptin sensitivity in pseudopregnant rats treated with chronic prolactin to mimic pregnancy.

Pregnancy in rodents is associated with hyperphagia, increased fat deposition, elevated leptin concentrations and insensitivity to the satiety action of leptin. To investigate the hormonal mechanisms involved in the development of this state of pregnancy-induced leptin resistance, we have used a pseudopregnancy rat model. We have previously demonstrated that pseudopregnant rats have a normal feeding response to leptin, although, if pseudopregnancy is extended using chronic i.c.v. ovine prolactin infusion along with progesterone implants, then leptin no longer suppresses food intake. The present study aimed to investigate the effect of chronically high lactogen levels, as seen in mid-pregnancy, on leptin-induced activation of hypothalamic Janus kinase/signal transducer and activator of transcription (JAK/STAT) signal transduction and mRNA expression of leptin (LepR-B) and prolactin (Prlr-L) receptors, using pseudopregnant rats chronically infused with ovine prolactin. Groups of virgin (dioestrous) and pseudopregnant rats were treated with chronic i.c.v. infusion of either prolactin (2.5μgμL-1 h-1 for 5days) or vehicle (artificial cerebrospinal fluid [aCSF]) via a minipump connected to a cannula surgically implanted into the lateral ventricle. Rats were fasted overnight and then received an i.c.v. injection of leptin (400ng) or vehicle (aCSF) and were perfused 30minutes later. In chronic vehicle-infused pseudopregnant rats, i.c.v. leptin increased the number of phosphorylated STAT3 positive cells in the arcuate nucleus and ventromedial nucleus (VMH) of the hypothalamus, similar to all acute-leptin treated virgin groups. This effect of leptin, however, was not observed in the pseudopregnant rats that were chronically infused with prolactin. A quantitative polymerase chain reaction analysis also showed decreased expression of LepR-B in the arcuate and VMH nuclei, as well as decreased Prlr-L in the arcuate nucleus of prolactin-infused "extended pseudopregnancy" rats. These data suggest that the attenuation of the leptin-induced suppression of food intake caused by chronically high lactogen levels in pseudopregnant rats is associated with impaired leptin-induced activation of the JAK/STAT pathway in specific hypothalamic nuclei.

Brain prolactin is involved in stress-induced REM sleep rebound

REM sleep rebound is a common behavioural response to some stressors and represents an adaptive coping strategy. Animals submitted to multiple, intermittent, footshock stress (FS) sessions during 96h of REM sleep deprivation (REMSD) display increased REM sleep rebound (when compared to the only REMSD ones, without FS), which is correlated to high plasma prolactin levels. To investigate whether brain prolactin plays a role in stress-induced REM sleep rebound two experiments were carried out. In experiment 1, rats were either not sleep-deprived (NSD) or submitted to 96h of REMSD associated or not to FS and brains were evaluated for PRL immunoreactivity (PRL-ir) and determination of PRL concentrations in the lateral hypothalamus and dorsal raphe nucleus. In experiment 2, rats were implanted with cannulas in the dorsal raphe nucleus for prolactin infusion and were sleep-recorded. REMSD associated with FS increased PRL-ir and content in the lateral hypothalamus and all manipulations increased prolactin content in the dorsal raphe nucleus compared to the NSD group. Prolactin infusion in the dorsal raphe nucleus increased the time and length of REM sleep episodes 3h after the infusion until the end of the light phase of the day cycle. Based on these results we concluded that brain prolactin is a major mediator of stress-induced REMS. The effect of PRL infusion in the dorsal raphe nucleus is discussed in light of the existence of a bidirectional relationship between this hormone and serotonin as regulators of stress-induced REM sleep rebound.

Opposing roles of Akt and STAT3 in the protection of the maternal heart from peripartum stress

Peripartum cardiomyopathy (PPCM) is a pregnancy-associated cardiomyopathy in previously healthy women. Mice with a cardiomyocyte-restricted deletion of signal transducer and activator of transcription-3 (STAT3, CKO) develop PPCM. PI3K-Akt signalling is thought to promote cardiac hypertrophy and protection during pregnancy. We evaluated the role of activated Akt signalling in the maternal heart postpartum. CKO mice were bred to mice harbouring an Akt transgene, specifically expressed in cardiomyocytes (CAkt(tg)) generating CKO; CAkt(tg), CAkt(tg), CKO, and wild-type sibling mice. CAkt(tg) and CKO;CAkt(tg) female mice developed PPCM with systolic dysfunction. Both genotypes displayed cardiac hypertrophy and lower capillary density, showed increased phosphorylation of p66 Src homology 2 domain containing protein and FoxO3A, and reduced expression of manganese superoxide dismutase as well as increased cathepsin D activity and increased miR-146a levels [indicative for generation of the anti-angiogenic 16 kDa prolactin (PRL)]. Cardiac inflammation and fibrosis was accelerated in CKO;CAkt(tg) and associated with high postpartum mortality. The PRL blocker, bromocriptine (BR), prevented heart failure and the decrease in capillary density in CKO;CAkt(tg) and CAkt(tg) mice. BR attenuated high mortality, up-regulation of CCL2, and cardiac inflammation as well as fibrosis in CKO;CAkt(tg). PRL infusion induced cardiac inflammation in CKO;CAkt(tg) independent of pregnancy. In neonatal rat cardiomyocytes, PRL and interferon γ (IFNγ) induced the expression of CCL2 via activation of Akt. Postpartum Akt activation is detrimental for the peripartum heart as it lowers anti-oxidative defence and in combination with low STAT3 conditions, accelerate cardiac inflammation and fibrosis. PRL and its cleaved 16 kDa form are central for Akt-induced PPCM as indicated by the protection from the disease by PRL blockade.

Extracellular Signal-regulated Kinase 5 (ERK5) Mediates Prolactin-stimulated Adult Neurogenesis in the Subventricular Zone and Olfactory Bulb

Prolactin-stimulated adult neurogenesis in the subventricular zone (SVZ) and olfactory bulb (OB) mediates several reproductive behaviors including mating/pregnancy, dominant male pheromone preference in females, and paternal recognition of offspring. However, downstream signaling mechanisms underlying prolactin-induced adult neurogenesis are completely unknown. We report here for the first time that prolactin activates extracellular signal-regulated kinase 5 (ERK5), a MAP kinase that is specifically expressed in the neurogenic regions of the adult mouse brain. Knockdown of ERK5 by retroviral infection of shRNA attenuates prolactin-stimulated neurogenesis in SVZ-derived adult neural stem/progenitor cells (aNPCs). Inducible erk5 deletion in adult neural stem cells of transgenic mice inhibits neurogenesis in the SVZ and OB following prolactin infusion or mating/pregnancy. These results identify ERK5 as a novel and critical signaling mechanism underlying prolactin-induced adult neurogenesis.

Prolactin Stimulates Precursor Cells in the Adult Mouse Hippocampus

In the search for ways to combat degenerative neurological disorders, neurogenesis-stimulating factors are proving to be a promising area of research. In this study, we show that the hormonal factor prolactin (PRL) can activate a pool of latent precursor cells in the adult mouse hippocampus. Using an in vitro neurosphere assay, we found that the addition of exogenous PRL to primary adult hippocampal cells resulted in an approximate 50% increase in neurosphere number. In addition, direct infusion of PRL into the adult dentate gyrus also resulted in a significant increase in neurosphere number. Together these data indicate that exogenous PRL can increase hippocampal precursor numbers both in vitro and in vivo. Conversely, PRL null mice showed a significant reduction (approximately 80%) in the number of hippocampal-derived neurospheres. Interestingly, no deficit in precursor proliferation was observed in vivo, indicating that in this situation other niche factors can compensate for a loss in PRL. The PRL loss resulted in learning and memory deficits in the PRL null mice, as indicated by significant deficits in the standard behavioral tests requiring input from the hippocampus. This behavioral deficit was rescued by direct infusion of recombinant PRL into the hippocampus, indicating that a lack of PRL in the adult mouse hippocampus can be correlated with impaired learning and memory.

Central Prolactin Modulates Insulin Sensitivity and Insulin Secretion in Diabetic Rats

Background: Prolactin secretion is self-regulating as it acts upon hypothalamic dopaminergic systems which inhibit prolactin release from the anterior pitutary. Circulating prolactin improves glucose homeostasis by increasing insulin action and secretion, but central prolactin effects on glucose homeostasis have not been examined. Here, we determined that chronic central infusion of prolactin modulates insulin resistance and β-cell function and mass in 90% of pancreatectomized diabetic male rats. Methods: Diabetic rats were divided into three groups according to the dose of intracerebroventricular infusion of prolactin during 4 weeks: (1) low-dose prolactin (Low-PRL; 0.1 µg/h), (2) high-dose prolactin (High-PRL; 1 µg/h) and (3) vehicle only (cerebrospinal fluid). Nondiabetic rats were centrally infused with the vehicle. Results: Chronic intracerebroventricular infusion of Low-PRL lowered body weight and epididymal fat pads by increasing hypothalamic dopamine levels that reduced serum prolactin levels and potentiated leptin signaling. However, High-PRL slightly exacerbated energy dysregulation, decreased hypothalamic dopamine levels, and elevated serum prolactin levels. Both dosages promoted β-cell mass but in a different manner: Low-PRL decreased β-cell apoptosis, whereas High-PRL increased its proliferation. However, only Low-PRL enhanced first-phase insulin secretion and improved insulin sensitivity at a hyperglycemic state in comparison to the control. Low-PRL also increased glucose infusion rates and decreased hepatic glucose output in hyperinsulinemic states, signifying an improvement in hepatic insulin sensitivity. However, High-PRL exacerbated hepatic insulin resistance compared with the control diabetic rats. Conclusions: In contrast to the exacerbation of insulin resistance caused by High-PRL, Low-PRL may improve energy and glucose metabolism by increasing hypothalamic dopamine levels in diabetic rats.

Kisspeptin Cells in the Ovine Arcuate Nucleus Express Prolactin Receptor but not Melatonin Receptor

Melatonin is secreted at night by the pineal gland and governs the reproductive system in seasonal breeders, such as sheep. The mechanism by which melatonin regulates reproduction is not known. The circannual rhythmicity of other factors, including prolactin, is also regulated by photoperiod via changes in melatonin secretion. In sheep, plasma prolactin levels are higher in the nonbreeding season than the breeding season. Kisspeptin, synthesised by neurones in the ovine arcuate nucleus (ARC) and preoptic area, is a key regulator of reproduction through stimulation of gonadotrophin-releasing hormone secretion and its expression in the ARC is reduced during the nonbreeding season. We hypothesised that kisspeptin expression is directly, or indirectly, regulated by melatonin and/or prolactin. We first examined the expression of melatonin receptor (MTNR1A) in kisspeptin (Kiss1 mRNA) neurones in the ARC of ovariectomised (OVX) sheep using double-label in situ hybridisation. MTNR1A mRNA was not expressed by kisspeptin neurones, whereas strong expression was detected in the pars tuberalis. We then examined the expression of the long-form prolactin receptor (PRLR-L) in ARC kisspeptin neurones. In OVX ewes, approximately 60% of kisspeptin neurones expressed PRLR-L mRNA at similar levels in the breeding and nonbreeding seasons. We then aimed to determine whether prolactin treatment during the breeding season regulates kisspeptin expression in the ARC. Continuous central infusion of prolactin (20 μg/h for 7 days) in oestradiol-treated OVX sheep did not alter Kiss1 mRNA expression or luteinising hormone secretion, although it induced substantial phosphorylated signal transducer and activator of transcription 5-immunoreactive nuclei staining in the mediobasal hypothalamus. We conclude that the seasonal change in kisspeptin neurones cannot be regulated directly by melatonin, although it may be a result of changes in prolactin levels. Despite this, kisspeptin expression was unchanged after exogenous prolactin treatment in breeding season ewes.

Hormone Interactions Regulating Energy Balance During Pregnancy

Appetite and food intake are increased during pregnancy, comprising an adaptive response that facilitates energy storage in preparation for the high metabolic demands of pregnancy and subsequent lactation. To maintain the increased energy intake in the face of increased adiposity and rising leptin levels, pregnant females become resistant to the central anorectic actions of leptin. In rats, pregnancy-induced leptin resistance is characterised by elevated neuropeptide Y and reduced pro-opiomelanocortin expression in the arcuate nucleus, reduced leptin receptor mRNA levels and suppression of leptin-induced phosphorylated signal transducer and activator of transcription-3 protein in the ventromedial hypothalamic nucleus, as well as a loss of anorectic responses to both leptin and alpha-melantocyte-stimulating hormone. Our recent data suggest that this leptin-resistance may also cause central insulin resistance and an altered peripheral glucose homeostasis. The specific hormone changes during pregnancy that might mediate these effects on leptin signalling are a current focus of investigation. In pseudopregnant rats, chronic i.c.v. infusion of ovine prolactin to mimic patterns of placental lactogen secretion that occur during pregnancy completely blocked the ability of leptin to suppress food intake. These data suggest that placental lactogen secretion may mediate the hormone-induced loss of response to leptin during pregnancy. This action of prolactin/placental lactogen appears to be mediated downstream of the primary leptin-responsive neurones in the mediobasal hypothalamus, possibly in the paraventricular nucleus. Our studies show complex hormone-induced adaptations in the normal hypothalamic pathways regulating body weight homeostasis during pregnancy.

Contradictory evidence concerning the "universal" role of growth hormone in the regulation of the enzyme activities of hepatic steroid metabolism.

Recent publications suggest that the sexual dimorphism observed in the activities of enzymes involved in drug and steroid metabolism in rat liver are due to sex-specific differences in the rate of growth hormone release. In this paper we set out to demonstrate that this hypothesis cannot be generalized, but has its limitations. Prepuberal hypophysectomy led to the expected "masculinization" of the activities of cytoplasmic 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSDH), microsomal 3 alpha-HSDH and microsomal 5 alpha-reductase which could be reversed by continuous infusion of human growth hormone (hGH). However, one activity did not conform to this pattern: cytoplasmic 17 beta-HSDH activity reacted to hypophysectomy with a "feminization" and was completely unaffected by hGH infusion. Moreover, microsomal 3 alpha-HSDH in hypophysectomized rats was "feminized" as efficiently by infusion of ovine prolactin (oPRL) as by hGH. Ablation of the pituitary caused loss of measurable cytoplasmic receptor oestrogen concentrations. The inability of either hypophyseal hormone to cause consistent and significant elevation of oestrogen receptor concentrations is probably due to the early age at which the animals were hypophysectomized.

Effects of Chronic Intracerebral Prolactin on the Oxytocinergic and Vasopressinergic System of Virgin Ovariectomized Rats

Chronic intracerebroventricular (icv) infusion of prolactin (PRL) into the cerebral ventricles and mimicking central hyperprolactinemia in lactation has recently been shown to reduce anxiety and neuronal as well as neuroendocrine responses to acute stressor exposure. Here, we studied the effects of icv PRL on the activity of the oxytocin (OXT) and arginine vasopressin (AVP) systems of virgin female, ovariectomized, estradiol-substituted Wistar rats. Ovine PRL was delivered via osmotic minipumps at 0.01, 0.1 or 1 μg/h for 5 days. Under basal conditions, both plasma OXT and AVP concentrations were increased after chronic PRL treatment (1 μg/h). At hypothalamic level, this was accompanied by an increased c-fos and OXT mRNA expression within the supraoptic nucleus, the main source of plasma OXT, whereas AVP mRNA levels remained unchanged. No effect of PRL on c-fos or on nonapeptide mRNA expression was found in the hypothalamic paraventricular nucleus. Moreover, chronic PRL abolished the rise in plasma OXT induced by acute exposure to 30 min restraint stress in vehicle-treated rats. However, restraint stress did not significantly alter OXT or AVP mRNA expression in the hypothalamus of either vehicle- or PRL-treated animals. From these results we conclude that brain hyperprolactinemia alters the synthetic activity of OXT neurons and the secretory performance of OXT and AVP neurons within the hypothalamus, resulting in elevated plasma concentrations of both hormones under basal conditions. These changes are comparable to adaptations seen in the female peripartum period.

Induction of Central Leptin Resistance in Hyperphagic Pseudopregnant Rats by Chronic Prolactin Infusion

Pregnancy in rats is associated with hyperphagia, increased fat deposition, and elevated plasma leptin concentrations. Elevated leptin would be expected to inhibit food intake, but hypothalamic leptin resistance develops around midpregnancy, allowing hyperphagia to be maintained and excess energy to be stored as fat in preparation for future metabolic demands of lactation. To investigate the hormonal mechanisms inducing leptin resistance during pregnancy, the anorectic response to leptin was examined during pseudopregnancy. Pseudopregnant rats have identical hormonal profiles to early pregnancy, but no placenta formation, allowing differentiation of maternal and placental hormone effects on appetite. To investigate the effect of leptin on food intake, d-9 pseudopregnant rats were injected with leptin (4 microg) via an intracerebroventricular (icv) cannula, and then food intake was measured 24 h later. Pseudopregnant rats were hyperphagic but had normal anorectic responses to leptin. We therefore hypothesized that a longer exposure time to high concentrations of progesterone might be required to mimic the leptin resistance that occurs on d 14 of pregnancy. Pseudopregnant rats were given progesterone to prolong pseudopregnancy beyond the time that leptin resistance develops during pregnancy. However, rats remained responsive to icv leptin. To model the placental lactogen secretion that occurs during pregnancy, pseudopregnant rats were given progesterone and chronic icv ovine prolactin infusion. Central icv injection of leptin had no effect on food intake in pseudopregnant rats receiving chronic ovine prolactin. These results suggest that chronically high lactogen levels, secreted by the placenta during the second half of pregnancy, induce central leptin resistance.

Prolactin/Leptin Interactions in the Control of Food Intake in Rats

Recent evidence suggests that the peptide hormone prolactin (PRL) modulates energy balance through a number of mechanisms, including acting in the brain to increase food intake. In the current studies, we first demonstrated that chronic infusions of PRL into the lateral ventricles increased food intake in cycling rats without disrupting estrous cyclicity. In subsequent experiments the hypothesis that at least part of PRL's ability to increase food intake resulted from PRL-induced leptin resistance was tested. Female rats given chronic infusions of PRL (5 microg/h) into the cerebral ventricles for 10 d did not show a reduction in food intake or body weight after a central injection of 4 microg murine leptin, whereas the expected reduction in both of these parameters was seen in vehicle-infused rats. Leptin injections were without effect on these parameters, whether they were administered to free feeding PRL-infused rats or after 24-h food deprivation. This lack of a behavioral response to leptin was accompanied by an attenuation in Fos induction and phosphorylation of signal transducer and activator of transcription 3 after leptin administration in PRL-infused rats in both the ventromedial hypothalamus and paraventricular hypothalamic nucleus.

Prolactin Induces Regional Vasoconstriction through the β2-Adrenergic and Nitric Oxide Mechanisms

Prolactin has been associated with many effects and has been implicated in the pathogenesis of pregnancy-related hypertensive disorders, although little is known about its vascular effects. The present study was designed to determine the primary effect of prolactin on regional vascular beds and the mechanisms involved. In 37 anesthetized pigs, the infusion of 0.17 mug/kg min of prolactin at constant heart rate and arterial pressure decreased coronary, mesenteric, renal, and iliac blood flow. This response was graded in further five pigs by increasing the infused dose of the hormone between 0.017 and 1 mug/kg min. In 22 of the 37 pigs, blockade of cholinergic receptors (five pigs) and of alpha-adrenoceptors (five pigs) did not affect the prolactin-induced vascular response, which was abolished by blockade of beta(2)-adrenoceptors (five pigs) and by blockade of vascular nitric oxide (NO) synthase (seven pigs). In 15 of the 37 pigs the increases in measured blood flows caused by iv infusion of isoproterenol (five pigs) and by intraarterial administration of acetylcholine (five pigs) and of sodium nitroprusside (five pigs) were significantly reduced by infusion of prolactin. Moreover, the treatment of porcine aortic endothelial cells by prolactin caused a reduction of NO production and of the phosphorylation of ERK, Akt, and p38, which was prevented by the concomitant treatment by the beta(2)-adrenergic agonist albuterol. The present study showed that iv infusion of prolactin primarily caused coronary, mesenteric, renal, and iliac vasoconstriction. These effects were brought about by the inhibition of a vasodilatory beta(2)-adrenergic receptor-mediated effect related to the NO intracellular pathway.

Prolactin Suppresses GnRH but Not TSH Secretion

Background/Aims: In animal models, prolactin increases tuberoinfundibular dopamine turnover, which has been demonstrated to suppress both hypothalamic GnRH and pituitary TSH secretion. To test the hypothesis that prolactin suppresses GnRH and TSH secretion in women, as preliminary evidence that a short-feedback dopamine loop also operates in the human, the effect of hyperprolactinemia on GnRH and TSH secretion was examined. Methods: Subjects (n = 6) underwent blood sampling every 10 min in the follicular phase of a control cycle and during a 12-hour recombinant human prolactin (r-hPRL) infusion preceded by 7 days of twice-daily subcutaneous r-hPRL injections. LH and TSH pulse patterns and menstrual cycle parameters were measured. Results: During the 7 days of r-hPRL administration, baseline prolactin increased from 16.0 ± 3.0 to 101.6 ± 11.6 µg/l, with a further increase to 253.7 ± 27.7 µg/l during the 12-hour infusion. LH pulse frequency decreased (8.7 ± 1.0 to 6.0 ± 1.0 pulses/12 h; p < 0.05) with r-hPRL administration, but there were no changes in LH pulse amplitude or mean LH levels. There were also no changes in TSH pulse frequency, mean or peak TSH. The decreased LH pulse frequency did not affect estradiol, inhibin A or B concentrations, or menstrual cycle length. Conclusion: These studies demonstrate that hyperprolactinemia suppresses pulsatile LH secretion but not TSH secretion and suggest that GnRH secretion is sensitive to hyperprolactinemia, but that TSH secretion is not. These data further suggest that the degree of GnRH disruption after 7 days of hyperprolactinemia is insufficient to disrupt menstrual cyclicity.

Rapid Eye Movement Sleep Is Reduced in Prolactin-Deficient Mice

Prolactin (PRL) is implicated in the modulation of spontaneous rapid eye movement sleep (REMS). Previous models of hypoprolactinemic animals were characterized by changes in REMS, although associated deficits made it difficult to ascribe changes in REMS to reduced PRL. In the current studies, male PRL knock-out (KO) mice were used; these mice lack functional PRL but have no known additional deficits. Spontaneous REMS was reduced in the PRL KO mice compared with wild-type or heterozygous littermates. Infusion of PRL for 11-12 d into PRL KO mice restored their REMS to that occurring in wild-type or heterozygous controls. Six hours of sleep deprivation induced a non-REMS and a REMS rebound in both PRL KO mice and heterozygous littermates, although the REMS rebound in the KOs was substantially less. Vasoactive intestinal peptide (VIP) induced REMS responses in heterozygous mice but not in KO mice. Similarly, an ether stressor failed to enhance REMS in the PRL KOs but did in heterozygous littermates. Finally, hypothalamic mRNA levels for PRL, VIP, neural nitric oxide synthase (NOS), inducible NOS, and the interferon type I receptor were similar in KO and heterozygous mice. In contrast, tyrosine hydroxylase mRNA was lower in the PRL KO mice than in heterozygous controls and was restored to control values by infusion of PRL, suggesting a functioning short-loop negative feedback regulation in PRL KO mice. Data support the notion that PRL is involved in REMS regulation.

Prolactin, a natriuretic hormone, interacting with the renal dopamine system

Although prolactin affects sodium and water transport across the plasma membrane and interacts with dopamine in the brain, its role in the kidney is unclear. Here we examined the effect of prolactin and its possible interaction with the intrarenal natriuretic hormone dopamine, on proximal tubular Na(+), K(+)-ATPase activity in vitro and renal function in anesthetized rats. Na(+), K(+)-ATPase activity was measured as ouabain-sensitive adenosine triphosphate (ATP) hydrolysis in microdissected proximal tubular segments. Renal function was studied during euvolemic conditions by conventional clearance techniques. Prolactin induced a dose-dependent inhibition of proximal tubular Na(+), K(+)-ATPase activity. A maximal inhibitory effect of 48% of control was observed at an in vitro prolactin concentration of 1 microg/mL. This effect was completely abolished by a dopamine D1 receptor antagonist. In tubules preincubated with inhibitors of aromatic amino acid decarboxylase (AADC), the rate-limiting enzyme in renal dopamine formation, prolactin had no effect on Na(+), K(+)-ATPase activity. In rats, prolactin infusion resulted in an increase in urinary sodium, potassium, and water excretion. These effects were also completely abolished by the D1 receptor antagonist. Prolactin had no significant effects on glomerular filtration rate (GFR) or mean arterial blood pressure. We conclude that prolactin is a natriuretic hormone which interacts with the renal dopamine system for its effects. The natriuretic response is associated with inhibition of proximal tubular Na(+), K(+)-ATPase activity.

Mathematical modelling of prolactin–receptor interaction and the corollary for prolactin receptor gene expression in skin

A mathematical model of prolactin regulating its own receptors was developed, and compared with experimental data on a qualitative level. The model incorporates the kinetics of prolactin–receptor interactions and subsequent signalling by prolactin–receptor dimers to regulate the production of receptor mRNA and hence the receptor population. The model relates changes in plasma prolactin concentration to prolactin receptor (PRLR) gene expression, and can be used for predictive purposes. The cell signalling that leads to the activation of target genes, and the mechanisms for regulation of transcription, were treated empirically in the model. The model's parameters were adjusted so that model simulations agreed with experimentally observed responses to administration of prolactin in sheep. In particular, the model correctly predicts insensitivity of receptor mRNA regulation to a series of subcutaneous injections of prolactin, versus sensitivity to prolonged infusion of prolactin. In the latter case, response was an acute down-regulation followed by a prolonged up-regulation of mRNA, with the magnitude of the up-regulation increasing with the duration of infusion period. The model demonstrates the feasibility of predicting the in vivo response of prolactin target genes to external manipulation of plasma prolactin, and could provide a useful tool for identifying optimal prolactin treatments for desirable outcomes.

The effects of prolonged, intracerebroventricular prolactin treatment on luteinizing hormone secretion, catecholaminergic activity and estrous behavior in ewes.

Searching for the role of prolactin (PRL) in controlling gonadotropic axis activity in sheep, we studied the effects of prolonged, intracerebroventricular (i.c.v.) PRL infusion on luteinizing hormone (LH) secretion and catecholaminergic activity in the hypothalamic infundibular nuclei/median eminence (IN/ME) in sexually active ewes during the periovulatory period. Three groups of animals received the following treatments: 1). i.c.v. infusion of PRL at a dose of 200 microg/day (Lower dose, n = 5); 2). i.c.v. infusion of PRL at a dose of 400 microg/day (Higher dose, n = 6), and 3). i.c.v. infusion of the vehicle (control, n = 5). Each dose of PRL was infused in a pulsatile manner, 4 x 50 microg/h and 4 x 100 microg/h, in 30-min intervals, respectively, during four consecutive days before oncoming ovulation. The estrous behavior of ewes following treatments was also monitored as a determinant of the GnRH/LH surge. Two series of blood collections were made in every ewe, the first on the day preceding the infusion (day 0 of the experiment), the second on the day after the infusion (day 5 of the experiment). In addition, on day 5 of the experiment, perfusions of the IN/ME were made by the push-pull method, either in control or lower dose-treated animals. It was shown that a significant (p < 0.01, p < 0.001) increase in tonic LH secretion during the periovulatory period remained in ewes irrespective of the kind of infusion. No statistical differences were found in LH pulse frequency, amplitude, or in the length of the pulse when compared with values from day 0 and 5 of the experiment within each group. A significant (p < 0.001) increase in IN/ME perfusate concentrations of dopamine and noradrenaline metabolites was noted in PRL-treated ewes in comparison with those in the control. The estrous behavior in PRL-treated animals was delayed for a few days, 3.80 +/- 0.80 days at the lower dose (p < 0.01), and 2.83 +/- 0.98 days at the higher dose (p < 0.05) in comparison with the control, 0.20 +/- 0.20 days. These data indicate that maintenance of an increased PRL concentration within the central nervous system (CNS) for a few days before oncoming ovulation has no inhibitory effect on tonic LH secretion. A few-day shift of the preovulatory GnRH/LH surge, as determined by estrous behavior, might, however, be a consequence of the PRL-induced increase in catecholamine turnover in the IN/ME.