Time course of the insensitivity of prolactin release to morphine administration in the lactating female rat

The effect of morphine on circulating levels of prolactin and growth hormone (GH) in the lactating female model was determined at various time intervals following the termination of suckling. Morphine administration did not produce an increase in prolactin levels when dams remained suckling. Four days after suckling was terminated, 50% of the dams tested showed a morphine induced prolactin increase. The prolactin secretory response to morphine gradually returned in dams, so that after 8 days of non-suckling, all animals tested showed a morphine induced prolactin increase. Consistent with the lack of prolactin stimulation, the tuberoinfundibular dopaminergic (TIDA) neurons, were insensitive to the morphine induced inhibition of activity during lactation. In contrast, circulating levels of GH were increased in these dams following morphine administration. These results suggest that the lactating female rat is insensitive to the mu mediated stimulation of prolactin release while suckling. However, sensitivity begins to return following at least 4 days of non-suckling.     

Changes in prolactin in peripheral plasma during lactation in the brushtail possum Trichosurus vulpecula

A heterologous double-antibody radioimmunoassay has been validated for prolactin in plasma and pituitary preparations of T. vulpecula. Serial dilutions of crude pituitary homogenates and plasmas from several marsupials and purified prolactin from the tammar, Macropus eugenii, showed parallel dose response curves. In both male and female possums plasma prolactin concentrations increased in response to a single intravenous injection of thyrotrophin releasing hormone. Plasma prolactin concentrations were measured in six lactating females (June-November) and in four non-lactating females (July-October). In the following year prolactin levels were also measured in 11 possums with young less than 50 days old and in 24 possums with young aged between 100 and 145 days. In early lactation prolactin concentrations were low (less than 8 ng/ml) but increased to high levels (greater than 30 ng/ml) by 120 days and remained high until about 160 days of lactation. Thereafter concentrations declined although the young continued to take milk from the mother for a further 30-50 days. The changes in plasma prolactin concentrations throughout lactation are very similar to those described for the tammar, and this unusual pattern appears to be common to marsupials. Non-lactating possums showed no consistent changes in plasma prolactin concentrations between July and October.     

Chronic estradiol exposure induces oxidative stress in the hypothalamus to decrease hypothalamic dopamine and cause hyperprolactinemia

Estrogens are known to cause hyperprolactinemia, most probably by acting on the tuberoinfundibular dopaminergic (TIDA) system of the hypothalamus. Dopamine (DA) produced by TIDA neurons directly inhibits prolactin secretion and, therefore, to stimulate prolactin secretion, estrogens inhibit TIDA neurons to decrease DA production. However, the mechanism by which estrogen produces this effect is not clear. In the present study, we used a paradigm involving chronic exposure to low levels of estradiol-17β (E(2)) to mimic prolonged exposures to environmental and endogenous estrogens. We hypothesized that chronic exposure to low levels of E(2) induces oxidative stress in the arcuate nucleus (AN) of the hypothalamus that contains TIDA neurons and causes nitration of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA. This results in a significant decrease in DA and consequently, hyperprolactinemia. To investigate this, adult, intact female cycling rats were implanted with slow-release E(2) pellets (20 ng/day) for 30, 60, or 90 days and were compared with old (16-18 mo old) constant estrous (OCE) rats. Chronic E(2) exposure significantly increased the expression of glial fibrillary acidic protein and the concentrations of interleukin-1β (IL-1β) and nitrate in the AN that contains perikarya of TIDA neurons and increased nitration of TH in the median eminence (ME) that contains the terminals. These levels were comparable to those seen in OCE rats. We observed a significant decrease in DA concentrations in the ME and hyperprolactinemia in an exposure-dependent manner similar to that seen in OCE rats. It was concluded that chronic exposure to low levels of E(2) evokes oxidative stress in the AN to inhibit TIDA neuronal function, most probably leading to hyperprolactinemia.     

Depletion of tuberoinfundibular dopamine does not restore gonadotropin secretion in ovariectomized hyperprolactinemic rats

The effect of depleting tuberoinfundibular dopamine (TIDA) on gonadotropin secretion was studied in rats made hyperprolactinemic by implantation of the prolactin and growth hormone secreting Furth MtTW15 tumor. Implants of the pituitary tumor prevented gonadotropin release in response to castration. Daily injection of 100 mg dl-alpha-methyl-para-tyrosine/kg bw which reduced TIDA levels in tumor bearing rats more than 90% did not restore gonadotropin release. It seems likely that the increased activity of the TIDA system does not mediate the suppression of gonadotropins during chronic hyperprolactinemia.     

The suckling-induced rise of plasma prolactin in lactating rats: its dependance on stage of lactation and litter size

The response of plasma prolactin in vigorous suckling was measured in lactating rats which had been isolated for 10-12 h from their offspring. Plasma prolactin was investigated during suckling at various stages of lactation. The results demonstrate that prolactin responds maximally to suckling already in the first days of lactation. In the second half of the lactation period, the prolactin rise in the plasma induced by suckling decreases gradually; this is not due to a reduced suck-intensity of older pups. A relationship is found between the height of the suckling-induced prolactin rise and litter size. The data suggest that during suckling in the first weeks of lactation the pituitary secretes large amounts of prolactin at a constant rate. It is speculated that in the first minutes of suckling, receptors may clear considerable amounts of released prolactin from the circulation.     

Involvement of hypothalamic dopamine in the regulation of prolactin secretion

The neuroendocrine control of prolactin (PRL) secretion is known to be a multifactorial process, but dopamine (DA) secreted by the tuberoinfundibular dopaminergic (TIDA) neurons of the hypothalamus is believed to exert a predominant inhibitory control on the secretion of PRL. The secretory activity of the TIDA neurons, including the rate of biosynthesis of DA and the rate of release of the neurohormone into hypophysial portal blood, can be readily evaluated in the rat. In most conditions in which an altered secretion of PRL has been documented, an altered secretory activity of the TIDA neurons has been found. When an acute reduction in the secretion of DA is observed, an increased secretion of PRL is associated, with an inverse relationship between DA and PRL concentrations in hypophysial portal and systemic blood, respectively. However, the secretion of PRL can be regulated by PRL itself through stimulation of the secretory activity of the TIDA neurons, and consequently hyperprolactinemia can be observed concomitantly with a sustained high secretion of DA, as seen after treatment with estrogen. The short loop feedback of PRL secretion seems to be impaired in the aging rat, since a sustained reduced hypothalamic secretion of DA is observed in spite of long-term hyperprolactinemia.     

Aminergic regulation of neuroendocrinological functions: theoretical background and some clinical examples

Remarkable progress has been made during recent years in the central regulation of the hypothalamic releasing and inhibiting factors and the respective anterior pituitary hormones. There are two nearly universal inhibitory organizations: short tuberoinfundibular dopamine (TIDA) neurons and somatostatinergic system originating from the periventricular hypothalamus and terminating to the median eminence. It is now known that e.g. dopamine, noradrenaline and acetylcholine enhance while 5-hydroxytryptamine and GABA inhibit somatostatin secretion. These transmitters are also involved in the regulation of all releasing factors and pituitary hormones. Clinical applications have been developed based on the regulation of prolactin and growth hormone. Inhibitory TIDA neurons are undoubtedly the major determinants of prolactin secretion. Hyperprolactinaemia is one of the most common endocrinological side-effects of the drugs antagonizing dopaminergic transmission. Expectedly, dopaminergic drugs (bromocryptine, lergotrile, piribedil, dopamine and levodopa) are quite effective in reducing high prolactin levels regardless of the reason. The secretion of growth hormone is predominantly under dual dopaminergic control: hypothalamic stimulation and pituitary inhibition. The former masters the function of the normal gland, while the peripheral inhibitory component takes over in acromegalic gland. Hence dopaminergic drugs are able to reduce elevated growth hormone levels in 30-50% of the acromegalic patients. In normal man, dopamine agonists increase growth hormone levels. An analogous situation can be seen in Cushing's disease regarding ACTH secretion.     

Effect of dopamine agonists or antagonists, TRH, stress and piglet removal on plasma prolactin concentrations in lactating gilts

The effect of dopamine agonists (ergocryptine), antagonists (chlorpromazine, haloperidol, reserpine, pimozide), thyrotropin releasing hormone or stress (restraint, piglet removal) on prolactin release was studied in primiparous lactating gilts. All animals were fitted with surgically implanted jugular catheters before farrowing. The only drug treatments which resulted in a significant change in PRL concentrations in blood were thyrotropin releasing hormone (increase) and ergocryptine (decrease). The results suggest that dopamine may not be the only regulator of prolactin in lactating pigs. Further studies are needed to identify drugs which would be useful in clinical situations for treatment of lactation failure due to low prolactin secretion. In the two stress-exposed groups, there was a gradual, steady decline in the plasma concentration of prolactin which resulted from loss of suckling contact with the piglets. Thus, snare restraint does not increase prolactin secretion in lactating sows confirming the results of other studies on pigs in different physiologic states.     

LHRH and LH release in the red fox Vulpes vulpes L

Pituitary responsiveness to exogenous LHRH was studied in vivo and in vitro in the female red fox, a mono-oestrous species. In vivo, the ability of the pituitary to release LH in response to a single injection of LHRH (2 micrograms/kg) was determined at various stages of the reproductive cycle. The greatest responsiveness is observed during the preovulatory period, the lowest during the luteal phase. During the anoestrus phase, the responsiveness is reduced by more than 50% in lactating females compared to non lactating females. In vitro, dispersed fox anterior pituitary cells were exposed four times to LHRH (10(-9) M), hourly, for 8 min. Pituitary cells were taken from lactating and non lactating females. The cells are not sensitive to LHRH in lactating females but become more and more sensitive after weaning. It is suggested the inhibitory influence of lactation could be the result of prolactin-ovarian steroids-gonadotrophins interactions.     

The effects of lactation on impulsive behavior in vasopressin-deficient Brattleboro rats

Vasopressin (AVP)-deficient Brattleboro rats develop a specific behavioral profile, which—among other things—include altered cognitive performance. This profile is markedly affected by alterations in neuroendocrine state of the animal such as during lactation. Given the links between AVP and cognition we hypothesized that AVP deficiency may lead to changes in impulsivity that is under cognitive control and the changes might be altered by lactation. Comparing virgin and lactating AVP-deficient female Brattleboro rats to their respective controls, we assessed the putative lactation-dependent effects of AVP deficiency on impulsivity in the delay discounting paradigm. Furthermore, to investigate the basis of such effects, we assessed possible interactions of AVP deficiency with GABAergic and serotonergic signaling and stress axis activity, systems playing important roles in impulse control. Our results showed that impulsivity was unaltered by AVP deficiency in virgin rats. In contrast a lactation-induced increase in impulsivity was abolished by AVP deficiency in lactating females. We also found that chlordiazepoxide-induced facilitation of GABAergic and imipramine-induced enhancement of serotonergic activity in virgins led to increased and decreased impulsivity, respectively. In contrast, during lactation these effects were visible only in AVP-deficient rats. These rats also exhibited increased stress axis activity compared to virgin animals, an effect that was abolished by AVP deficiency. Taken together, AVP appears to play a role in the regulation of impulsivity exclusively during lactation: it has an impulsivity increasing effect which is potentially mediated via stress axis-dependent mechanisms and fine-tuning of GABAergic and serotonergic function.     

Alterations in concentrations of dihydroxyphenylacetic acid in the median eminence of rats euthanatized with pentobarbital

Concentrations of dopamine (DA) and one of its major metabolites, dihydroxyphenylacetic acid (DOPAC), were determined in selected brain regions of rats that were euthanatized either by decapitation or by intravenous injections of pentobarbital or Fatal Plus, a commercial preparation that contains pentobarbital. When compared with values in decapitated brains, pentobarbital increased the concentration of DOPAC in the median eminence, which contains terminals of tuberoinfundibular dopaminergic (TIDA) neurons. Fifteen minutes of restraint reduced the concentration of DOPAC in the median eminence of rats killed by decapitation or by injections of pentobarbital, indicating that pentobarbital does not mask restraint-induced decrease in TIDA neuronal activity. In contrast, none of the manipulations altered DA or DOPAC concentrations in the striatum, which contains terminals of nigrostriatal dopaminergic neurons. Thus, changes in the concentrations of DOPAC in the median eminence (an index of TIDA neuronal activity) induced by stress can be detected in rats euthanatized by either decapitation or an injection of pentobarbital.     

Effects of reproductive condition and dominance rank on cortisol responsiveness to stress in free‐ranging female rhesus macaques

The hypothalamic–pituitary–adrenal (HPA) axis modulates individuals' physiological responses to social stress, which is an inevitable aspect of the daily lives of group‐living animals. Previous nonhuman primate studies have reported that sex, age, rank, and reproductive condition influence cortisol levels under stressful conditions. In this study we investigated cortisol responses to stress among 70 multiparous, free‐ranging female rhesus macaques (Macaca mulatta) on the island of Cayo Santiago, PR. Plasma cortisol samples were collected in two consecutive years under similar conditions. Twenty‐two females were sampled both years, and most of those females were lactating in only one of the years. Individual differences in cortisol levels were stable across years, even though reproductive condition changed for most individuals. No relationship was found between age or social rank and cortisol levels. Of the females that changed reproductive conditions, cortisol levels were higher when they were lactating than when they were cycling, and the amount of change in cortisol from cycling to lactating was greatest for low‐ranking individuals. Heightened reactivity to stress during lactation may be the result of concerns about infant safety, and such concerns may be higher among low‐ranking mothers than among higher ranking mothers. Psychosocial stress and hyperactivation of the HPA axis during lactation can suppress immune function and increase vulnerability to infectious diseases, thus explaining why adult females in the free‐ranging rhesus macaque population on Cayo Santiago have a higher probability of mortality during the birth season than during the mating season. Am. J. Primatol. 72:559–565, 2010. © 2009 Wiley‐Liss, Inc.     

The effect of cholecystokinin, bombesin and calcitonin on food intake in virgin, lactating and postweaning female rats

During lactation food intake increases greatly without an accompanying large increase in body weight; therefore, this physiological state is an excellent example of non-obese hyperphagia. In the present study, we found that cholecystokinin (CCK-8) decreased food intake in lactating and virgin female rats. However, female rats were more resistant to the effect of CCK on eating following weaning of the pups. Bombesin (BB) suppressed food intake in virgin female rats and in lactating rats during early and mid lactation. Rats were resistant to its satiating effect during late lactation and during the postweaning period. Calcitonin potently suppressed food intake in virgin, lactating and postweaning rats. The present findings suggest that CCK and bombesin decrease food intake more effectively in virgin female rats and during earlier phases of lactation than during late lactation or postweaning.     

Ultrasonic cries from infant rats stimulate prolactin release in lactating mothers

Lactating female rats, separated from their litters for 6 hr, showed a dramatic elevation in plasma prolactin following a 15-min playback of ultrasonic vocalizations recorded from 7-day-old pups. Virgin females exhibited a smaller but still significant prolactin response to recorded pup calls. Control recordings of either background noise or adult ultrasonic vocalizations (22–26 kHz) had no effect on prolactin secretion even in lactating females. These results demonstrate that infant vocalizations can act as a stimulus for prolactin release and suggest that such communications may play a role in the maintenance of normal lactation.     

Interference with prolactin release and the maternal behavior of female rats

The role of prolactin in maintaining the maternal behavior of the rat was investigated. Ergocornine, a drug that interferes with the release of prolactin from the anterior pituitary, was injected daily into postpartum females for a period of 21 days. Those receiving ergocornine did not differ significantly from control females on any measure of maternal behavior, the control females having received either ergocornine plus prolactin or simply the vehicle. Since both lactation and the decidual cell response to uterine traumatization were inhibited after ergocornine, and since each were at least partially reversed by exogenous prolactin, it was evident that ergocornine interfered successfully with the postpartum release of prolactin. That at the same time maternal behavior was unaffected, supports the conclusion that prolactin is not essential in maintaining the maternal responsivity of the postpartum female rat.     

Infertility in transgenic female mice with human growth hormone expression: evidence for luteal failure

Introduction of the human growth hormone (hGH) gene fused with mouse metallothionein I promoter into domestic mice leads to ectopic synthesis of hGH, marked stimulation of somatic growth, and female sterility. Transgenic females (produced by mating transgenic males to normal females) mated but failed to become pregnant or pseudopregnant as evidenced by the recurrence of vaginal plugs every 5-7 days. Daily injections of 1 mg progesterone, starting on day 1 postcoitum (p.c.), maintained pregnancy, suggesting that the sterility of these animals is due to inadequate luteal function. In ovariectomized female transgenic mice, median eminence (ME) turnover of dopamine (DA) was increased, and plasma prolactin (PRL) levels were reduced, presumably because of the known lactogenic activity of hGH in rodents. From these observations we suspected that either 1) the corpora lutea of these animals are unresponsive to lactogenic hormones, or 2) hGH by stimulating tuberoinfundibular dopaminergic (TIDA) neurons interferes with the increase in PRL release that normally follows mating and this, in turn, leads to luteal failure. To distinguish between these possibilities, transgenic females were treated with PRL-secreting ectopic pituitary transplants from normal females of the same strain on day 1 p.c. Eight of ten treated females became pregnant and delivered litters. We conclude that infertility of transgenic female mice with hGH expression is due to activation of the TIDA system, suppression of endogenous PRL release, and luteal deficiency.     

The ability of prolactin to change the sensitivity of the pituitary of the lactating rat to luteinising hormone releasing hormonein vitro

The ability of prolactin to influence the responsiveness of the lactating rat pituitary to luteinising hormone releasing hormone has been examinedin vitro. The pituitary responsivenessin vivo to luteinising hormone releasing hormone decreased as a function of increase in the lactational stimulus. Prolactin inhibited the spontaneousin vitro release of luteinising hormone and follicle stimulating hormone to a small extent, from the pituitary of lactating rats with the suckling stimulus. However, it significantly inhibited the release of these two hormones from luteinising hormone releasing hormone-stimulated pituitaries. The responsiveness of pituitaries of rats deprived of their litter 24 h earlier, to luteinising hormone releasing hormone was also inhibited by prolactin, although minimal. It was concluded that prolactin could be influencing the functioning of the pituitary of the lactating rat by (a) partially suppressing the spontaneous release of gonadotropin and (b) inhibiting the responsiveness of the pituitary to luteinising hormone releasing hormone.     

Prolactin receptors in the brain during pregnancy and lactation: implications for behavior

Numerous studies have documented prolactin regulation of a variety of brain functions, including maternal behavior, regulation of oxytocin neurons, regulation of feeding and appetite, suppression of ACTH secretion in response to stress, and suppression of fertility. We have observed marked changes in expression of prolactin receptors in specific hypothalamic nuclei during pregnancy and lactation. This has important implications for neuronal functions regulated by prolactin. In light of the high circulating levels of prolactin during pregnancy and lactation and the increased expression of prolactin receptors in the hypothalamus, many of these functions may be enhanced or exaggerated in the maternal brain. The adaptations of the maternal brain allow the female to exhibit the appropriate behavior to feed and nurture her offspring, to adjust to the nutritional and metabolic demands of milk production, and to maintain appropriate hormone secretion to allow milk synthesis, secretion, and ejection. This review aims to summarize the evidence that prolactin plays a key role in regulating hypothalamic function during lactation and to discuss the hypothesis that the overall role of prolactin is to organize and coordinate this wide range of behavioral and neuroendocrine adaptations during pregnancy and lactation.     

Cytological and immunocytochemical studies of the anterior pituitary gland of the beagle bitch during various reproduction phases]

The changes in anterior pituitary (AP) of pregnant and lactating dogs as compared with pituitary of animals in metestrus-anestrus phase are described with special reference to the relative proportion, topography and morphology of prolactin cells, somatotrophs, corticotrophs, thyrotrophs and gonadotrophs. For demonstration of these cells, suitable histological, histochemical and immunoenzyme cytochemical methods are used. The prolactin cells show progressive hyperplasia during pregnancy, so that at the end of this phase and during lactation, they comprise the most predominant glandular cells in AP. At the same time, they reveal massive hypertrophy with marked morphological features of high secretory activity, After transient or continous interruption of the suckling stimulus they show signs of functional inhibition on involution. The corticotrophs appear at 20. and 30. days of pregnancy to be relatively increased in number. While in the last third of pregnancy and during lactation, they only seem to be more active than those in pituitary of metestrus-anestrus dogs. The somatotrophs appear to be progressively reduced in relative number during pregnancy and lactation. However, they show some morphological signs of active secretion. The thyrotrophs did not show any morphological alterations during the different reproductive phases. The gonadotrophs reveal during pregnancy, especially at 30. day morphological signs of stimulation. On the contrary they appear atrophied during lactation. This may be a result of suckling stimulus and morphological expression of the inverse relationship in the secretion pattern of gonadotrophins and prolactin in dogs during suckling. The estrogen and progesterone levels in plasma as well as the changes in their relative concentrations may largely account for the structural changes on AP of pregnant dogs. However, neuroendocrine reflexes (e.g. suckling stimulus) seem to be of a great importance for the maintainance of stimulation of prolactin cells during lactation.     

Effects of early life social stress on endocrinology,maternal behavior,and lactation in rats

Exposure to early life stress is a predictor of mental health disorders, and two common forms of early life stress are social conflict and impaired maternal care, which are predominant features of postpartum mood disorders. Exposure of lactating female rats to a novel male intruder involves robust social conflict and induces deficits in maternal care towards the F1 offspring. This exposure is an early life social stressor for female F1 pups that induces inefficient lactation associated with central changes in oxytocin (OXT), prolactin (PRL), and arginine vasopressin (AVP) gene expression in adult F1 females.