Suckling-induced Prolactin Release Research Articles

Insulin-like growth factor I and its binding protein-3 are regulators of lactation and maternal responsiveness

Adaptation to motherhood includes maternal behaviour and lactation during the postpartum period. The major organizing centres of maternal behaviour and lactation are located in the hypothalamic medial preoptic area (MPOA) and the arcuate nucleus, respectively. Insulin-like growth factor I (IGF-I) is an effector of the growth hormone axis; however, its function in the brain is largely unexplored. We identified increased maternal IGF binding protein-3 (IGFBP-3) expression in preoptic rat microarray data and confirmed it by RT-PCR. In situ hybridization histochemistry showed markedly elevated IGFBP-3 expression in the MPOA and the arcuate nucleus in rat dams. Prolonged intracerebroventricular injection of IGF-I or antagonism of brain IGFBP-3 with an inhibitor (NBI-31772) using osmotic minipumps increased pup retrieval time, suggesting reduced maternal motivation. Suckling-induced prolactin release and pup weight gain were also suppressed by IGF-I, suggesting reduced lactation. In addition, IGF-I-induced tyrosine hydroxylase expression and its specific phosphorylation in tuberoinfundibular dopaminergic neurons suppress prolactin secretion. Thus, IGF-I may inhibit both behavioural and lactational alterations in mothers. Neurons in the MPOA and arcuate nuclei express IGFBP-3 during the postpartum period to neutralize IGF-I effects. IGFBP-3 can prevent the blockade of maternal behaviour and lactation exerted by IGF-I, suggesting a novel modulatory mechanism underlying the behavioural and hormonal effects during central maternal adaptations.

Maternally involved galanin neurons in the preoptic area of the rat.

Recent selective stimulation and ablation of galanin neurons in the preoptic area of the hypothalamus established their critical role in control of maternal behaviors. Here, we identified a group of galanin neurons in the anterior commissural nucleus (ACN), and a distinct group in the medial preoptic area (MPA). Galanin neurons in ACN but not the MPA co-expressed oxytocin. We used immunodetection of phosphorylated STAT5 (pSTAT5), involved in prolactin receptor signal transduction, to evaluate the effects of suckling-induced prolactin release and found that 76% of galanin cells in ACN, but only 12% in MPA were prolactin responsive. Nerve terminals containing tuberoinfundibular peptide 39 (TIP39), a neuropeptide that mediates effects of suckling on maternal motivation, were abundant around galanin neurons in both preoptic regions. In the ACN and MPA, 89 and 82% of galanin neurons received close somatic appositions, with an average of 2.9 and 2.6 per cell, respectively. We observed perisomatic innervation of galanin neurons using correlated light and electron microscopy. The connection was excitatory based on the glutamate content of TIP39 terminals demonstrated by post-embedding immunogold electron microscopy. Injection of the anterograde tracer biotinylated dextran amine into the TIP39-expressing posterior intralaminar complex of the thalamus (PIL) demonstrated that preoptic TIP39 fibers originate in the PIL, which is activated by suckling. Thus, galanin neurons in the preoptic area of mother rats are innervated by an excitatory neuronal pathway that conveys suckling-related information. In turn, they can be topographically and neurochemically divided into two distinct cell groups, of which only one is affected by prolactin.

Thalamic neuropeptide mediating the effects of nursing on lactation and maternal motivation

Nursing has important physiological and psychological consequences on mothers during the postpartum period. Tuberoinfundibular peptide of 39 residues (TIP39) may contribute to its effects on prolactin release and maternal motivation. Since TIP39-containing fibers and the receptor for TIP39, the parathyroid hormone 2 receptor (PTH2 receptor) are abundant in the arcuate nucleus and the medial preoptic area, we antagonized TIP39 action locally to reveal its actions. Mediobasal hypothalamic injection of a virus encoding an antagonist of the PTH2 receptor markedly decreased basal serum prolactin levels and the suckling-induced prolactin release. In contrast, injecting this virus into the preoptic area had no effect on prolactin levels, but did dampen maternal motivation, judged by reduced time in a pup-associated cage during a place preference test. In support of an effect of TIP39 on maternal motivation, we observed that TIP39 containing fibers and terminals had the same distribution within the preoptic area as neurons expressing Fos in response to suckling. Furthermore, TIP39 terminals closely apposed the plasma membrane of 82% of Fos-ir neurons. Retrograde tracer injected into the arcuate nucleus and the medial preoptic area labeled TIP39 neurons in the posterior intralaminar complex of the thalamus (PIL), indicating that these cells but not other groups of TIP39 neurons project to these hypothalamic regions. We also found that TIP39 mRNA levels in the PIL markedly increased around parturition and remained elevated throughout the lactation period, demonstrating the availability of the peptide in postpartum mothers. Furthermore, suckling, but not pup exposure without physical contact, increased Fos expression by PIL TIP39 neurons. These results indicate that suckling activates TIP39 neurons in the PIL that affect prolactin release and maternal motivation via projections to the arcuate nucleus and the preoptic area, respectively.

Biosynthesis of proTRH-derived peptides in prohormone convertase 1 and 2 knockout mice

Prohormone convertases (PCs) 1 and 2 are the primary endoproteases involved in the post-translational processing of proThyrotropin Releasing Hormone (proTRH) to give rise to TRH and other proposed biologically active non-TRH peptides. Previous evidence suggests that PC1 is responsible for most proTRH cleavage events. Here, we used the PC1 and PC2 knockout (KO) mouse models to examine the effects of PC1 or PC2 loss on proTRH processing. The PC1KO mouse presented a decrease in five proTRH-derived peptides, whereas the PC2KO mouse showed only lesser reduction in three TRH (Gln-His-Pro), TRH-Gly (Gln-His-Pro-Gly), and the short forms preproTRH178–184 (pFQ7) and preproTRH186–199 (pSE14) of pFE22 (preproTRH178–199). Also, PC1KO and not PC2KO showed a decrease in pEH24 indicating that PC1 is more important in generating this peptide in the mouse, which differs from previous studies using rat proTRH. Furthermore, downstream effects on thyroid hormone levels were evident in PC1KO mice, but not PC2KO mice suggesting that PC1 plays the more critical role in producing bioactive hypophysiotropic TRH. Yet loss of PC1 did not abolish TRH entirely indicating a complementary action for both enzymes in the normal processing of proTRH. We also show that PC2 alone is responsible for catalyzing the conversion of pFE22 to pFQ7 and pSE14, all peptides implicated in regulation of suckling-induced prolactin release. Collectively, results characterize the specific roles of PC1 and PC2 in proTRH processing in vivo.

Tuberoinfundibular peptide of 39 residues is activated during lactation and participates in the suckling-induced prolactin release in rat

Tuberoinfundibular peptide of 39 residues is activated during lactation and participates in the suckling-induced prolactin release in rat

Tuberoinfundibular Peptide of 39 Residues (TIP39): A New Player in the Translation of Sensory Input to Prolactin Release during Lactation

Lactation is an important reproductive state for all mammalian species. Nourishment of the young is provided by maternal milk and thus competent lactation is necessary for the survival of most mammalian species. Although not now required for survival of human infants, breast milk is considered the most nutritionally complete foodfornewborns.Prolactinplaysessentialrolesinmammary gland development and the production of nutritional components of maternal milk, most notably milk proteins. The stimulus for prolactin release is the suckling of the young on sensory mechanoreceptors in the mammaryglandtogenerateaneuralsignal,whichistranslated into a hormonal signal with the suckling-induced release of prolactin and oxytocin. The neural signal is sent through sensory tracts in the spinal cord, brainstem, and thalamus and eventually elicits the release of prolactin from the pituitary gland through the involvement of hypothalamic neuronal groups (1–5). The control of prolactin secretion during this reproductive process is complex and at times seems to have redundancyingrainedinthesystem(6–8).Thus,allofthe playersinthisimportantreproductiveprocesshavenotyet been identified and placed in their proper sequence. The

Tuberoinfundibular Peptide of 39 Residues Is Activated during Lactation and Participates in the Suckling-Induced Prolactin Release in Rat

Tuberoinfundibular peptide of 39 residues (TIP39) and the PTH-2 receptor (PTH2R) constitute a peptide-receptor neuromodulator system. Based on the abundance of TIP39 fibers and axonal terminals as well as PTH2R-containing neurons and their processes in the hypothalamic para- and periventricular and arcuate nuclei TIP39 has been suggested to play a role in neuroendocrine regulation. We showed previously that TIP39 expression decreased dramatically by adulthood. In the present study, using in situ hybridization histochemistry, real-time RT-PCR, and immunohistochemistry, we found that TIP39 mRNA and peptide expression levels are markedly elevated in the posterior intralaminar complex of the thalamus (PIL) of lactating dams, one of the three locations of TIP39-containing cell bodies in the brain. In addition, in mother rats, these TIP39 neurons showed Fos expression in response to pup exposure. Transection of TIP39 fibers originating in the PIL resulted in an ipsilateral disappearance of TIP39 immunoreactivity throughout the mediobasal hypothalamus of mother rats, suggesting that TIP39 fibers there arise from the PIL. To elucidate the function of TIP39 activation in dams, mothers separated from their pups for 4 h on postpartum d 9 received injection of a PTH2R antagonist into the lateral ventricle 5 min before returning the pups. Blood samples were taken seven times during the experimental period through jugular cannulae. The PTH2R antagonist administered in two different concentrations markedly inhibited suckling-induced elevation of plasma prolactin levels in a dose-dependent manner. These results suggest that TIP39 neurons in the PIL may regulate suckling-induced prolactin release in rat dams.

Mu and kappa opioid receptor expression in the mediobasal hypothalamus and effectiveness of selective antagonists on prolactin release during lactation

Endogenous opioid peptides are involved in prolactin release during lactation, in part by decreasing tuberoinfundibular dopaminergic (TIDA) neuronal activity. Both mu (μ) and kappa (κ) opioid receptors have a role in the suckling-induced prolactin rise after 4–5 h up deprivation. The aim of this study was to investigate effects of μ opioid receptor antagonist, β-funaltrexamine (β-FNA), and κ opioid receptor antagonist, nor-binaltorphimine (nor-BNI), on prolactin secretion and TIDA neuronal activity in lactating rats after 18 h pup deprivation. After 4 h separation from pups, the suckling-induced prolactin rise was abolished by 16 μg nor-BNI and 5 μg β-FNA, coincident with increased dihydroxyphenylacetic acid (DOPAC):dopamine ratio in the stalk-median eminence (SME). However, after 18 h pups separation, these same doses of nor-BNI and β-FNA did not alter the prolactin surge or DOPAC:dopamine ratios in the SME. Higher doses of nor-BNI (32 μg) and β-FNA (10 μg) were required to inhibit suckling-induced prolactin secretion. β-FNA (10 μg) increased the DOPAC:dopamine ratio in the SME, whereas nor-BNI (32 μg) treatment had no effect. The μ and κ opioid receptor mRNA levels in the mediobasal hypothalamus were similar to suckled control rats after 4 h pup deprivation, but increased 1.4-fold after 18 h pup deprivation. These data support involvement of endogenous opioidergic systems in the suckling-induced prolactin rise after a prolonged (18 h) period of pup deprivation, as well as the shorter (4 h) pup deprivation period previously reported. Suppression of TIDA neuronal activity likely played a part in μ opioid receptor input to the suckling-induced prolactin rise after both 4 h and 18 h separation, whereas non-dopaminergic input was implicated with κ opioid receptors after 18 h pup deprivation. Increased μ and κ opioid receptors gene expression in the mediobasal hypothalamus may contribute to reduced effectiveness of opioid receptor antagonists to block suckling-induced prolactin release after 18 h pup deprivation.

Intracerebroventricular injection of a parathyroid hormone 2 receptor antagonist abolishes suckling induced prolactin release

Intracerebroventricular injection of a parathyroid hormone 2 receptor antagonist abolishes suckling induced prolactin release

A direct neuronal connection between the subparafascicular and ventrolateral arcuate nuclei in non-lactating female rats. Could this pathway play a role in the suckling-induced prolactin release?

The neuronal pathways, through which prolactin secretion is regulated during lactation, have still not been fully explored. Studies indicate that the suckling stimulus travels through the spinal cord, the brain stem, and then reaches the hypothalamus. The focus of this present experiment is to further explore the neuronal connections between the brain stem and the arcuate nucleus that may be involved in suckling-induced prolactin release. Ante- and retrograde tracing techniques were used. To chemically characterize the explored neurons neuropeptide immunohistochemistry was applied. Previous studies have indicated that the peripeduncular nucleus is a relay of the suckling stimulus in the midbrain, conveying the information to the hypothalamus. In our experiments, we have found an additional cell group in the subparafascicular parvocellular nucleus located just behind the posterior thalamus that projects to the arcuate neurons. The injection of the retrograde tracer into the ventrolateral part of the arcuate nucleus labeled cells in the lateral subdivision of the subparafascicular parvocellular nucleus. Anterograde tracing from the subparafascicular parvocellular nucleus resulted in fiber labeling in the arcuate nucleus in close apposition with dynorphin immunopositive neurons. Double labeling revealed that a subpopulations of the subparafascicular parvocellular neurons projecting to the arcuate nucleus contained tuberoinfundibular peptide of 39 residues or calcitonin gene-related peptide. The presented findings suggest that the ascending fibers from the subparafascicular parvocellular nucleus might be in the pathway involved in the suckling-induced prolactin release.

Identification of salsolinol in the mediobasal hypothalamus of lactating ewes and its relation to suckling-induced prolactin and GH release

The push-pull perfusions of the infundibular nucleus-median eminence (IN/ME) were made in lactating ewes (n=7) twice, to identify dopamine (DA)-derived salsolinol and the changes in its extracellular concentration in response to suckling. The perfusate collecting period in every ewe consisted of control non-suckling period, 1000-1230 h (five perfusates), and suckling period, 1230-1500 h (next five perfusates). Simultaneously, blood samples were collected from 1000 to 1500 h at 10-min intervals. The perfusate concentrations of salsolinol and DA were measured by HPLC, and plasma prolactin and GH concentrations were assayed by the RIA. Mean concentrations of salsolinol in perfusates collected from the anterior and posterior parts of the IN/ME (according to post-mortem localization of a perfusion site) increased significantly (P<0.05 and P<0.001 respectively) during the suckling period, when compared with those noted during the non-suckling period. While no DA was found in the anterior part, only vestigial amounts of DA were found in a few perfusates collected from the posterior part. Salsolinol was not detected in the IN/ME of ewes 10 weeks after weaning (seasonal anoestrus). Mean plasma prolactin and GH concentrations during suckling were significantly (P<0.001) higher than those noted during the non-suckling period. In conclusion, our current study reveals that salsolinol is present in the IN/ME of lactating ewes and that its extracellular concentration increases during suckling. Moreover, it supports the role of salsolinol as a neurotransmitter involved in the regulatory process of prolactin secretion at least during lactation.

Effects of methanolic extract of Asparagus pubescens root on sexual behavior and pituitary hormone secretion on Wistar rats during pregnancy and lactation

We investigated the effect of methanolic extract of Asparagus pubescens root on sexual behavior and on pituitary hormone secretion during pregnancy and lactation on Wistar rats. Different doses (0.25, 0.5, 1.0 and 1.5 g/kg) of the extract, given in a single bolus dose or in four (divided) daily injections (0.0625, 0.125, 0.25 and 0.375 mg/(kg day)), inhibited sexual behavior when given to proestrous females in a dose-dependent manner, with the high doses (1.0–1.5 g/kg) inhibiting significantly the lordosis quotient. All treated females showed aggressive behavior towards the males to a similar extent irrespective of dose. Fertilization rate, pregnancy, delivery and litter size were normal. Birth weight and growth rates of the pups were also unaffected indicating no deleterious effects of extract on offspring development. The extract had significant effects on preovulatory luteinizing hormone (LH), prolactin (PRL) and progesterone (P4) release. Divided doses of 1.0 and 1.5 g/kg significantly decreased preovulatory LH, PRL and P4 release. Administration of 0.5 or 1.5 g/kg in bolus dose, produced significant inhibition of preovulatory LH and PRL while 1.5 g/kg had no effect. Progesterone was not modified while 1.0 g/kg dose caused a decrease in GH. 0.25 g/kg produced a paradoxical increase in preovulatory PRL secretion, also seen on day 4 of pregnancy. During pregnancy, both dose regimens were effective in inhibiting the afternoon peaks in prolactin secretion at all dose levels with the exception of 0.25 g/kg. There were no effects on the second half of pregnancy or on the suckling-induced PRL release on day 3 postpartum. Circulating GH was scarcely affected on day 3 postpartum. All the results taken together, indicate that the contraceptive effects of the extract may be exerted through interference with neural mechanisms that control preovulatory hormone release and sexual behavior.

Lactation reduces prolactin levels in reproductively experienced female rats

Long-term alterations in prolactin (PRL) secretion following reproductive experience have been demonstrated in both women and female rats. In the rat, these changes include decreased PRL secretion in response to a dopamine antagonist challenge following ovariectomy, decreased post-coital diurnal and nocturnal prolactin surges in multigravid versus primigravid females, as well as decreased suckling-induced prolactin release in multiparous versus primiparous females. To date, there have been no studies examining PRL secretion following reproductive experience in cycling female rats. Studies in women, however, have demonstrated a reduction in basal PRL secretion during the menstrual cycle. The purpose of the present work was to determine whether similar changes occur in the rat during the estrous cycle and to what extent lactation is involved in these effects. In addition to examining PRL, potential parity-induced changes in estradiol secretion were also studied. The findings revealed a significant decrease in PRL levels during the afternoon of proestrus, which was only observed in primiparous females that had lactated. Significant differences in estradiol secretion were not detected following reproductive experience. Thus, a reduction in the PRL surge on the afternoon of proestrus is a consequence of reproductive experience that requires both pregnancy and lactation.

Generation of thyrotropin-releasing hormone receptor 1-deficient mice as an animal model of central hypothyroidism.

To provide an animal model of central hypothyroidism, mice deficient in the TRH-receptor 1 (TRH-R1) gene were generated by homologous recombination. The pituitaries of TRH-R1-/- mice are devoid of any TRH-binding capacity, demonstrating that TRH-R1 is the only receptor localized on TRH target cells of the pituitary. With the exception of some retardation in growth rate, TRH-R1-/- mice appear normal, but compared with control animals they exhibit a considerable decrease in serum T(3), T(4), and prolactin (PRL) levels but not in serum TSH levels. In situ hybridization histochemistry and real-time RT-PCR analysis revealed that in adult TRH-R1-/- animals TSHbeta-mRNA expression is not impaired whereas PRL mRNA and GH mRNA levels are considerably reduced compared with control mice. The numbers of thyrotropes, somatotropes, and lactotropes, however, are not affected by the deletion of the TRH-R1 gene. The mutant mice are fertile, and the dams nourish their pups well, indicating that TRH is not a decisive factor for suckling-induced PRL release. In situ hybridization and quantitative RT-PCR analysis, furthermore, revealed that, as in control animals, pituitary PRL-mRNA expression in TRH-R1-/- is considerably increased during lactation, albeit strongly reduced as compared with lactating control animals.

Brain Structures Mediating the Suckling Stimulus‐Induced Release of Prolactin

Suckling-induced prolactin release is a widely studied neuroendocrine reflex, comprising a neural afferent and a humoral efferent component. The information on the brain structures involved in this reflex is fairly limited. The present studies focused on this question. The following hypothalamic interventions were made in lactating rats and the dams were tested for the suckling-induced prolactin response: (i) unilateral or (ii) bilateral frontal cuts at the level of the anterior and posterior hypothalamus; (iii) administration of 5,7-dihydroxytryptamine or (iv) 6-hydroxydopamine into the hypothalamic paraventricular nucleus (PVN) to destroy serotonergic and catecholaminergic innervation of the cell group, respectively; (v) lesion of the medial subdivision of the PVN; and (vi) horizontal knife cuts below the PVN. Bilateral posterior and bilateral or unilateral anterior frontal cuts caused blockade of the suckling-induced release of prolactin. Likewise, most dams receiving 5,7-dihydroxytryptamine in the PVN did not respond to the suckling stimulus. Immunocytochemistry revealed that, in those rats which did not show a rise in plasma prolactin, there were almost no serotonergic fibres and terminals in the PVN, while in dams which exhibited a response, numerous serotonergic elements were evident. 6-Hydroxydopamine treatment did not cause significant alteration in the prolactin response. Lesion of the medial, largely parvocellular subdivision of the PVN, or horizontal knife cuts below this cell group, blocked the hormone response. The findings demonstrate for the first time that: (i) interruption of the connections between the brain stem and the hypothalamus interferes with the prolactin response to the suckling stimulus; (ii) serotonergic fibres terminating in the hypothalamic PVN are involved in the mediation of the suckling stimulus; and (iii) within the PVN, neurones in the medial, largely parvocellular subdivision of the cell group take part in the transfer of the neural signal, eventually inducing prolactin release.

Dual role of glucocorticoids in suckling-induced prolactin secretion.

The exact contribution of corticosteroids to the control of prolactin secretion in lactating rats is poorly understood. Therefore, the present studies were focused on the effect of adrenalectomy and dexamethasone treatment on the suckling-induced prolactin release. Animals were adrenalectomized on the 3rd day of lactation and tested on the 7th day of lactation. In adrenalectomized animals, the suckling stimulus failed to induce the characteristic increase in plasma prolactin levels. Dexamethasone pretreatment (400 microg/kg b.w. s.c. 24, 48, 72 h before testing) of adrenalectomized rats restored this prolactin response. The same treatment with dexamethasone given to control animals attenuated the suckling stimulus induced prolactin response. The present findings indicate that corticosteroids are essential for a basic prolactin response of lactating rats.

Chronic alcohol exposure and lactation: Extended observations

Previous results from our laboratory have indicated that chronic (8 days) alcohol administration inhibits suckling-induced prolactin (PRL) release in response to 30 min of suckling. In addition, chronic alcohol administration to dams resulted in growth retardation of their litters. The present study was done to examine how an extended period of suckling (120 min) affected suckling-induced PRL release after chronic alcohol exposure. In addition, it was also examined whether the growth retardation observed during alcohol exposure persisted after alcohol infusions were discontinued. Dams were implanted with an atrial catheter on day 3 of lactation and saline or alcohol (1.0- or 2.0-g/kg BW) was administered daily for 8 days (lactation days 5 through 12). Following administration of the initial alcohol dose, the infusion was continued at rates required to maintain blood alcohol levels (BALs) for 4 h each day. Testing took place on day 12. As previously reported, suckling-induced PRL release was inhibited in dams receiving 2.0-g/kg alcohol after 30 min of suckling. However, after 120 min of suckling, PRL release in these dams was much higher than in either control or 1.0-g/kg alcohol dams. In addition, while the body weights of litters of dams administered 2.0-g/kg alcohol were reduced compared to litters of dams in the other two groups on days 8–16, their body weights rebounded and were not different from the other litters on days 18 or 20.

Maternal exposure to atrazine during lactation suppresses suckling-induced prolactin release and results in prostatitis in the adult offspring.

The availability of prolactin (PRL) to the neonatal brain is known to affect the development of the tuberoinfundibular (TIDA) neurons and, as a consequence, lead to alterations in subsequent PRL regulation. Without early lactational exposure to PRL (derived from the dam's milk), TIDA neuronal growth is impaired and elevated PRL levels are present in the prepubertal male. These observations, combined with the finding that alterations in PRL secretion (i.e., hyperprolactinemia) in the adult male rat have been implicated in the development of prostatitis, led us to hypothesize that early lactational exposure to agents that suppress suckling-induced PRL release would lead to a disruption in TIDA development, altered PRL regulation, and subsequent prostatitis in the male offspring. To test this hypothesis, suckling-induced PRL release was measured in Wistar dams treated twice daily with the herbicide atrazine (ATR, by gavage, on PND 1-4 at 0, 6.25, 12.5, 25, and 50 mg/kg body weight), or twice daily with the dopamine receptor agonist bromocriptine (BROM, sc, at 0.052, 0.104, 0.208, and 0.417 mg/kg); BROM is known to suppress PRL release. Similarly, atrazine has also been reported to suppress PRL in adult females. Serum PRL was measured on PND 3 using a serial sampling technique and indwelling cardiac catheters. A significant rise in serum PRL release was noted in all control females within 10 min of the initiation of suckling. Fifty-mg/kg ATR inhibited suckling-induced PRL release in all females, whereas 25 and 12.5 mg/kg ATR inhibited this measure in some dams and had no discernible effect in others. The 6.25 mg/kg dose of ATR was without effect. BROM, used here as a positive control, also inhibited suckling-induced PRL release at doses of 0.104 to 0.417 mg/kg, with no effect at 0.052 mg/kg. To examine the effect of postnatal ATR and BROM on the incidence and severity of inflammation (INF) of the lateral prostate of the offspring, adult males were examined at 90 and 120 days. While no effect was noted at 90 days of age, at 120 days, both the incidence and severity of prostate inflammation was increased in those offspring of ATR-treated dams (25 and 50 mg/kg). The 12.5 mg/kg ATR and the two highest doses of BROM increased the incidence, but not the severity, of prostatitis. Combined treatment of ovine prolactin (oPRL) and 25 or 50 mg/kg ATR on PND 1-4 reduced the incidence of inflammation observed at 120 days, indicating that this increase in INF, seen after ATR alone, resulted from the suppression of PRL in the dam. To determine whether or not there is a critical period for these effects, dams were dosed with 25 and 50 mg/kg on PND 6-9 and PND 11-14. Inflammation was increased in those offspring from dams treated on PND 6-9, but this increase was not significant. Dosing on PND 11-14 was without effect. These data demonstrate that ATR suppresses suckling-induced PRL release and that this suppression results in lateral prostate inflammation in the offspring. The critical period for this effect is PND 1-9.

Endogenous opioid peptides contribute to suckling-induced prolactin release by suppressing tyrosine hydroxylase activity and messenger ribonucleic acid levels in tuberoinfundibular dopaminergic neurons.

The endogenous opioid peptides have been implicated in the control of the suckling-induced PRL rise during lactation. This study examined the role of the endogenous opioid peptides in suppressing tuberoinfundibular dopaminergic neuronal activity during lactation. In the first experiment, lactating rats were constantly exposed to pups. Naloxone (NAL; 60 mg/kg x h; i.v.), an opioid receptor antagonist, or saline was infused for 12 h. Blood was collected before and at 2-h intervals during the infusion. NAL suppressed circulating PRL levels to less than 36% of control values at 4, 6, 8, and 12 h after the onset of the infusion. Tyrosine hydroxylase (TH) activity in the stalk-median eminence and TH messenger RNA signal levels in the arcuate nucleus were determined at the end of the NAL infusion. TH activity and TH messenger RNA signal levels were increased 2.5- and 2.7-fold, respectively, after the 12-h NAL infusion. Even though the time spent with their pups was similar between the two groups, the pups in the NAL-treated group failed to gain weight during the 12-h NAL infusion period, whereas the control litters (8 pups) gained 5 g. In a second experiment, pups were removed from the dams before the 12-h NAL infusion and were returned after 11 h. Blood was collected before the infusion, at 3-h intervals during the pup separation period, and at 15-min intervals after reunion with the pups. Plasma PRL in control and NAL-treated rats was low (1-15 ng/ml) and similar during the separation period. The suckling-induced PRL surge in NAL-treated rats was markedly attenuated to 9-25% of control levels (350-650 ng/ml). After a 1-h suckling episode, TH activity in the stalk-median eminence of NAL-treated rats was 4.5-fold greater than controls. Litter weight gains were significantly less in NAL-treated rats during the 1-h suckling episode. These data indicate that the endogenous opioid peptides are an integral component for increasing PRL release in response to suckling and they act to decrease tuberoinfundibular dopaminergic neuronal activity during lactation, in part, by suppressing TH gene expression.

Endogenous Opioid Peptides Contribute to Suckling-Induced Prolactin Release by Suppressing Tyrosine Hydroxylase Activity and Messenger Ribonucleic Acid Levels in Tuberoinfundibular Dopaminergic Neurons

Endogenous Opioid Peptides Contribute to Suckling-Induced Prolactin Release by Suppressing Tyrosine Hydroxylase Activity and Messenger Ribonucleic Acid Levels in Tuberoinfundibular Dopaminergic Neurons