Stress-induced Prolactin Secretion Research Articles

Glucocorticoid Fast Feedback Inhibition of Stress-Induced ACTH Secretion in the Male Rat: Rate Independence and Stress-State Resistance.

Normal glucocorticoid secretion is critical for physiological and mental health. Glucocorticoid secretion is dynamically regulated by glucocorticoid-negative feedback; however, the mechanisms of that feedback process are poorly understood. We assessed the temporal characteristics of glucocorticoid-negative feedback in vivo using a procedure for drug infusions and serial blood collection in unanesthetized rats that produced a minimal disruption of basal ACTH plasma levels. We compared the negative feedback effectiveness present when stress onset coincides with corticosterone's (CORT) rapidly rising phase (30 sec pretreatment), high plateau phase (15 min pretreatment), or restored basal phase (60 min pretreatment) as well as effectiveness when CORT infusion occurs after the onset of stress (5 min poststress onset). CORT treatment prior to stress onset acted remarkably fast (within 30 sec) to suppress stress-induced ACTH secretion. Furthermore, fast feedback induction did not require rapid increases in CORT at the time of stress onset (hormone rate independent), and those feedback actions were relatively long lasting (≥15 min). In contrast, CORT elevation after stress onset produced limited and delayed ACTH suppression (stress state resistance). There was a parallel stress-state resistance for CORT inhibition of stress-induced Crh heteronuclear RNA in the paraventricular nucleus but not Pomc heteronuclear RNA in the anterior pituitary. CORT treatment did not suppress stress-induced prolactin secretion, suggesting that CORT feedback is restricted to the control of hypothalamic-pituitary-adrenal axis elements of a stress response. These temporal, stress-state, and system-level features of in vivo CORT feedback provide an important physiological context for ex vivo studies of molecular and cellular mechanisms of CORT-negative feedback.

Inhibition of Stress-Induced Adrenocorticotropin and Prolactin Secretion Mediating Hypophysiotropic Factors by Antagonist of AMPA Type Glutamate Receptor

Glutamate is the dominant excitatory neurotransmitter in a large number of physiological processes including neuroendocrine regulation. Some pharmacological studies have shown that different subtypes of glutamate receptor, such as the N-methyl-D-aspartic acid (NMDA) and alpha-amino-3-hydroxy-5-methy-4-isoxazolepropionic acid (AMPA) receptors, are involved in stress-induced adrenocorticotropin (ACTH) and prolactin secretion. However, the roles of the respective glutamate receptors and the mechanism of ACTH and prolactin secretion during stress via these receptors have not been investigated in detail. In the present study, we evaluated the role of AMPA-type glutamate receptor in ACTH and prolactin regulation under restraint stress in adult male rats. Male rats pretreated with a selective AMPA receptor antagonist, 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX; 50 microg), through a lateral ventricle cannula were stressed by immobilization. Administration of NBQX inhibited ACTH and prolactin secretion in response to restraint stress. However, NBQX had no significant effects on the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis, as measured by the accumulation of 3, 4-dihydroxyphenylalanine (DOPA). In addition, administration of NBQX suppressed stress-induced prolactin secretion in the male rats pretreated with alpha-MT, an inhibitor of dopamine synthesis, and infused with dopamine solution (2.5 microg/200 microl/10 min). These results indicated that the effects of NBQX on prolactin secretion might be mediated by non-dopamine mechanisms. The contents of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) in the median eminence (ME) of the male rats decreased during restraint stress; however, the fluctuations in CRH and AVP were eliminated by NBQX administration. These results suggest that stress-induced ACTH and prolactin release mediated by neurotransmission via AMPA receptors might be partly attributable to hypophysiotropic regulatory factors in the hypothalamus.

Ovarian Steroids But Not the Locus Coeruleus Regulate Stress‐Induced Prolactin Secretion in Female Rats

Stress has been proposed to stimulate prolactin release if its prestress levels are low, or to inhibit it if they are elevated, but the role of ovarian-steroid fluctuations in the prolactin stress response is not yet clearly understood. Because the noradrenergic nucleus locus coeruleus has been implicated in stress responses and generation of prolactin surges in female rats, the present study aimed to evaluate stress-induced prolactin secretion under different hormonal conditions, determining the effect of locus coeruleus lesion on each response. Blood samples were withdrawn from a jugular vein catheter 5 and 2 min before and 2, 5, 10, 15 and 30 min after ether stress in male rats, female rats during the oestrous cycle and ovariectomised rats treated with oil (OVX), oestradiol (OVE) or oestradiol plus progesterone (OVEP). Increased Fos immunoreactivity demonstrated locus coeruleus activation following ether stress. Ether stress increased both low (at 16.00 h in males, in OVX and on dioestrous and at 11.00 h on pro-oestrous and oestrous) and high plasma prolactin (at 16.00 h on oestrous and in OVE), but it decreased elevated prolactin levels during the afternoon on pro-oestrous and in OVEP. Locus coeruleus lesion prevented prolactin surges during the afternoon on pro-oestrous, oestrous, OVE and OVEP but did not modify either pattern (i.e. increase or decrease) or degree of prolactin stress response under any condition studied. The present data therefore suggest that oestradiol and progesterone modulate stress-induced prolactin secretion, regardless of its prestress levels. Moreover, the locus coeruleus is probably not involved in prolactin response to stress and most likely has a specific role in prolactin surges induced by ovarian steroids.

Prolactin and corticosterone secretion in response to acute stress after paraventricular nucleus lesion by ibotenic acid

The cellular organization of the paraventricular nucleus (PVN) is complex and eight distinct regions have been identified by Nissl staining. Three consist of magnocellular neurons and five of parvocellular neurons. Ibotenic acid, a glutamate analogue, is a toxin with neuroexcitatory properties which acts on N-methyl-D-aspartate and metabotropic receptors. Depending on the dose used, ibotenic acid causes extensive damage of parvocellular neurons of the paraventricular nucleus but preserves magnocellular neurons and passage fibers, in contrast to electrolytic lesions, which causes diffuse and nonspecific destruction. We studied the prolactin (PRL) and corticosterone secretion in response to acute stress induced by exposure to the ether, 3 weeks after selective neurotoxic lesion of parvocellular neurons of the paraventricular nucleus by microinjection of ibotenic acid. There was no significant difference in the basal levels of PRL and corticosterone between control and lesioned animals. The plasma PRL increased in the sham and lesioned groups after stress of similar manner. However, the increase in plasma corticosterone in response to stress was significantly higher in lesioned animals. In conclusion, the selective lesion of parvocellular neurons of the PVN did not change basal or stress induced PRL secretion but it caused hypersensitivity of the hypothalamus-pituitary-adrenal axis 3 weeks later, probably by corticotropin releasing hormone (CRH) from hypothalamic areas others than parvocellular neurons of the PVN; hypersensitivity of corticotropes to the secretagogues others than CRH; or hyperresponsiveness of AVP receptors in the adenohypophysis. Furthermore, we cannot rule out a putative inhibitory factor of the hypothalamus-pituitary axis produced by parvocellular neurons of the PVN. This factor modulator of corticotropin secretion could be absent after recuperation of the response of the hypothalamus-pituitary axis to the stress.

Effects of N-methyl-D-aspartic acid and kainic acid on prolactin secretion in hyper- and hypoprolactinaemic conditions.

The stimulatory and inhibitory effects of N-methyl-D-aspartic acid (NMDA) and kainic acid on prolactin (PRL) secretion have been correlated with the serum prolactin concentrations before drug administration. In the present experiments, we analysed the role of NMDA and kainic acid in PRL secretion in females with different serum concentrations of PRL. Hypoprolactinaemic females were obtained by ovariectomy or after administration of diethyldithiocarbamate (an inhibitor of dopamine-beta-hydroxylase). Chronic hyperprolactinaemia was induced by neonatal administration of testosterone or oestradiol and acute hyperprolactinaemia was induced either by administration of alpha-methyl-p-tyrosine (an inhibitor of tyrosine hydroxylase) or by ether exposure. To analyse the role of dopamine in the effects of NMDA, we measured pituitary concentrations of dopamine after NMDA treatment and the effects of pretreatment with domperidone. (1) NMDA, but not kainic acid, stimulated PRL release in cyclic females. This effect was independent of serum PRL concentrations and was not accompanied by a decrease in pituitary concentrations of dopamine. (2) NMDA did not change PRL secretion in neonatally androgenized females, whereas NMDA and kainic acid inhibited PRL release in neonatally oestrogenized females. The inhibitory effects of NMDA and kainic acid were blocked by domperidone. (3) Kainic acid inhibited PRL secretion in prepubertal hyper- and hypoprolactinaemic rats. (4) Hyperprolactinaemia induced by ether stress was counteracted by administration of NMDA and kainic acid. (a) NMDA has a dual effect on prolactin secretion that is independent of prior prolactin concentrations and of dopamine activity, but kainic acid is only inhibitory. (b) The stimulatory or inhibitory effects of NMDA and kainic acid on PRL secretion were not strictly related to basal PRL concentrations and necessarily involved a change in the secretion of prolactin releasing factors, as no correlations were observed between changes in pituitary concentrations of dopamine and serum PRL concentrations. (c) Females rendered hyperprolactinaemic by neonatal administration of testosterone or oestradiol responded differently after NMDA administration. (d) NMDA and kainic acid blocked the mechanisms involved in stress-induced PRL secretion.

Effect of Nω‐nitro‐l‐arginine methyl ester, a nitric oxide synthesis inhibitor, on stress‐ and morphine‐induced prolactin release in male rats

1. The effect of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) was investigated on stress- and morphine-induced prolactin (PRL) secretion in vivo in male rats, by use of a stress-free blood sampling and drug administration method by means of a permanent indwelling catheter in the right jugular vein. 2. Three doses of L-NAME were tested (1, 10 and 30 mg kg-1) and were given intraperitoneally one hour before blood sampling; control rats received saline. After the first blood sample, rats received an initial intravenous injection of morphine (3, 6 or 12 mg kg-1) or were subjected to immobilization stress. In the case of a morphine administration, rats received a second dose of morphine (3, 6 or 6 mg kg-1, respectively) 90 min later, when tolerance had developed, while rats subjected to immobilization stress received 6 mg kg-1 morphine 90 min after onset of stress. 3. L-NAME had no effect on basal plasma PRL concentration. However, it potentiated acute morphine-induced PRL secretion and attenuated the subsequent tolerance in a dose-dependent way. Immobilization stress-induced PRL secretion was inhibited dose-dependently by L-NAME, as was its subsequent tolerance to morphine; however, in this case, in a reversed dose-dependent way. 4. When the highest dose of morphine (12 mg kg-1) was combined with the highest dose of L-NAME pretreatment (30 mg kg-1), all rats showed a dramatic potentiation of the morphine-induced PRL rise compared to controls. Moreover, all of these rats died within 90 min after the administration of morphine. 5. These results show that NO plays a role in the acute opioid action on PRL release during stress as well as in the development of tolerance to the opioid effect, and some possible mechanisms are discussed.

Effect of modified brain histamine contents on prolactin and thyrotropin secretion in male rats

Effects of modified brain histamine contents on thyrotropin and prolactin secretion were studied in male rats. Under basal conditions the histamine content in the hypothalamus was approximately 8-10-fold higher than that in the striatum and the rest of the brain. L-histidine (1000 mg/kg, ip), a histamine precursor, and metoprine (20 mg/kg, ip), an inhibitor of histamine methyltransferase, elevated histamine content in the brain by 65% and 167%, respectively. When the treatments were given together an additive effect (119-250% increase) on brain histamine was observed. Metoprine significantly decreased serum prolactin levels, while L-histidine had no effect. This effect of metoprine was not modified by treatment with L-histidine. Thus, metoprine has an inhibitory effect on prolactin secretion that is not related to elevated brain histamine contents. The increased brain histamine content after L-histidine treatment had no effect on prolactin secretion. Basal levels of serum thyrotropin were decreased by both L-histidine and metoprine, L-histidine being more potent. In rats treated with alpha-fluoromethylhistidine, an inhibitor of L-histidine decarboxylase, the cold-induced (rats kept for 60 min at +4 degrees C) thyrotropin secretion was increased while the stress-induced prolactin secretion was decreased. In these rats, metoprine did not affect thyrotropin release but blunted the prolactin response. In conclusion, endogenous histamine inhibits thyrotropin secretion but does not affect prolactin release. Owing to its other effects, metoprine is not suitable as a tool to elevate endogenous histamine contents in the brain, at least when the regulation of anterior pituitary hormone release is being studied.

Histamine- and stress-induced prolactin secretion: importance of vasopressin V1- and V2-receptors.

We investigated the involvement of arginine vasopressin (AVP) V1- and V2-receptors in the prolactin (PRL) secretory response to histamine (HA) or restraint stress stimulation in conscious male rats by selective blockade of AVP receptors using different antagonists. Histamine (270 nmol) administered intracerebroventricularly or 5 min of restraint stress stimulated PRL secretion 10-14-fold. Pretreatment with the selective V1-receptor antagonists [1-(p-t-butyl-beta-mercapto-beta, beta-cyclopentamethylene propionic acid)-2-(O-methyl)tyrosine-8-D-arginine]vasopressin or [1-(beta-mercapto-beta, beta-cyclopentamethylene propionic acid)-2-(O-methyl)tyrosine-8-arginine]vassopressin inhibited the PRL response to HA and restraint stress in a dose-dependent manner with maximal inhibition of 60%. The effect of the two antagonists was identical when equipotent antivasopressor doses were administered. The selective V2-receptor antagonist [1-(beta-mercapto-beta, beta-cyclopentamethylene propionic acid)-2-D-isoleucine-4-isoleucine-8-arginine]vasopressin was unable to inhibit the PRL response significantly. Combined administration of the V1-receptor antagonist [1-(p-t-butyl-beta-mercapto-beta, beta-cyclopentamethylene propionic acid-2-(O-methyl)tyrosine-8-D-arginine]vasopressin and the V2-receptor antagonist inhibited the PRL response to HA to the same extent as that observed when the V1-antagonist was administered alone. None of the antagonists used had any effect on basal PRL secretion. We conclude that AVP seems to play a role in the mediation of HA- and restraint stress-induced secretion of PRL, and that the AVP receptor involved is primarily of the V1-type or similar to this.

Effect of acute stress on the expression of hypothalamic messenger ribonucleic acids encoding the endogenous opioid precursors preproenkephalin A and proopiomelanocortin

In addition to the release of adenohypophysial hormones adrenocorticotropin and β-endorphin, most types of acute stress induce rapid release of prolactin (PRL) from the anterior pituitary lobe. Endogenous opioid peptides are believed to participate in the stress-induced PRL secretion via an action within the central nervous system. In the present study, we have investigated the effect of acute stress on anterior pituitary PRL secretion and the hypothalamic expression of messenger ribonucleic acids (mRNAs) encoding precursors of the endogenous opioids Met-enkephalin and β-endorphin. Adult male rats were subjected to 1 h of restraint and the stress-induced rise in plasma PRL was measured both during and after termination of the stress paradigm. Using quantitative in situ hybridization histochemistry, it was observed that levels of proenkephalin A mRNA increased significantly within the medial parvocellular subset of the hypothalamic paraventricular nucleus, and within the arcuate nucleus levels of proopiomelanocortin (POMC) mRNA were slightly, but significantly, increased. The employed stress paradigm also induced an elevation of anterior pituitary levels of PRL and POMC mRNAs. The present data suggest that restraint stress activates gene expression of endogenous opioid systems in the hypothalamus and that the employed stress paradigm is of sufficient magnitude to stimulate both mRNA expression and release of PRL in the anterior pituitary lobe.

Prolactin secretion in sheep after dehydration followed by restraint or administration of ovine corticotrophin-releasing factor.

Plasma concentrations of prolactin were measured in male sheep (wethers, n = 8) during 120 min exposure to mild physical stress (restraint), and also following I.V. injection of 30 micrograms ovine corticotrophin-releasing factor (CRF), when the animals were water replete and when they had been deprived of water for 48 h. Restraint stress produced a small increase in prolactin secretion (n.s.) when the animals were euhydrated and a large increase (P less than 0.001) when they were dehydrated. Administration of CRF had no effect on prolactin concentrations in either experimental condition. In a further study in which euhydrated animals (n = 6) were subjected to restraint while receiving infusions of vasopressin (1 microgram/h), there was no enhancement of basal or stress-induced prolactin secretion. Thus, dehydration enhances stress-induced prolactin release in sheep through a process that does not involve a pituitary action of CRF or circulating vasopressin.

Inhibitory effects of centrally administered |ASU1–7| eel calcitonin on basal and stimulated prolactin release in rats

We investigated the effects of /ASU1-7/eel calcitonin (ASU1-7eelCT) on basal and stimulated prolactin (PRL) release in male rats. /ASU1-7/eelCT was administered intracerebroventricularly (icv) into freely moving rats with indwelling catheters. The administration of /ASU1-7/eelCT (2.5 micrograms/rat, icv) significantly inhibited basal PRL secretion. When PRL secretion was stimulated by exposing rats to restraint stress, /ASU1-7/eelCT (250 ng; 800 ng; 2.5 micrograms/rat, icv) dose-relatedly inhibited the PRL surges at 10 min after stress. The same doses of icv /ASU1-7/eelCT were effective in inhibiting morphine (6 mg/kg, intracarotid, ia-induced PRL release. No effect on stress-induced PRL secretion was observed when the peptide was administered intracarotid at the dose of 10 micrograms/rat. These results demonstrate that /ASU1-7/eelCT, as we previously observed with salmon calcitonin (sCT), has central inhibitory activity on PRL secretion, probably through enhancement of hypothalamic inhibitory pathways involved in the control of PRL.

The effect of bombesin on basal, α-methyl-p-tyrosine, haloperidol, morphine, bremazocine and stress-induced prolactin secretion

Intravenously administered bombesin lowered basal PRL levels in conscious male rats and prevented the morphine, bremazocine and stress-induced PRL secretion. The same dose of bombesin had no effect on PRL levels in α-methyl-p-tyrosine pretreated rats and did not affect haloperidol-stimulated PRL release. These results show that bombesin given intravenously acts as an inhibitor of PRL secretion and suggests that it does not act on the lactotrope itself but rather by an increase of the inhibitory dopaminergic tone.

Pharmacological studies on stress-induced renin and prolactin secretion: Effects of benzodiazepines, Naloxone, propranolol and diisopropyl fluorophosphate

Stress-induced renin and prolactin secretion was investigated using a conditioned emotional response paradigm. Three minutes after placement in a chamber the rats received an electric shock to their feet via the grid floor, then were immediately returned to their home cage. This procedure was repeated for 3 consecutive days. On the fourth day, instead of receiving an electric shock, they were removed after 3 min and sacrificed by decapitation. Control rats were treated identically with the exception that shock was not administered at any time. There was a significant increase in plasma renin activity and prolactin level in the stressed rats. The administration of the antianxiety drugs chlordiazepoxide (10 mg/kg i.p.) or midazolam (0.125–2 mg/kg i.p.) blocked the stress-induced increase in prolactin levels but not the stress-induced rise in plasma renin activity. Administration of the β-blocker propranolol (1 mg/kg i.p.) inhibited, but did not completely block, stress-induced rise in plasma renin activity and had no effect on stress-induced prolactin secretion. The opiate antagonist naloxone (0.1–10 mg/kg i.p.) and the acetylcholinesterase inhibitor diisopropyl fluorophosphate (0.5 mg/kg i.p.) did not block stress-induced renin of prolactin secretion. It is concluded that stress-induced prolactin secretion is regulated by a benzodiazepine-mediated mechanism and that stress-induced renin but not prolactin secretion is mediated in part via β-receptors.

Effects of naloxone on basal and stress-induced prolactin secretion, in intact, hypothalamic deafferentated, adrenalectomized, and dexamethasone-pretreated male rats

The effects of naloxone (Nal) on basal and stress-induced PRL secretion were investigated in intact (N) adult male rats, as were its effects in rats with complete hypothalamic deafferentiation (CHD), in adrenalectomized (adrenX) rats, and in rats pretreated with dexamethasone (dex). Forty-five minutes subsequent to Nal administration (5mg/kg, BW, IP) basal serum levels of PRL were reduced by approximately 25% (p<0.05), in both N and CHD groups. PRL secretory responses to acute exposure to both photic and acoustic stress were markedly attenuated in Nal-injected, as compared to vehicle-injected animals. Basal serum PRL concentrations were elevated by 40% in adrenX rats (p<0.05), as compared to controls. In (p<0.05) in dex-treated rats, as compared to controls. In both these experimental groups, Nal administration caused significant reductions in serum PRL. This study demonstrates that stress-induced, as well as basal PRL secretion, is attenuated by Nal, and points to a hypothalamic site of action in this regard. Furthermore, these Nal effects are independent of glucocorticoid interactions with the CNS.

Suppression of serum prolactin by naloxone but not anti-β-endorphin antiserum in stressed and unstressed rats

The role of endogenous opioids in the regulation of tonic and stress-induced prolactin secretion was studied in male rats. Animals with chronically indwelling intra-atrial catheters were used and served as their own controls. Intravenous injection of a potent rabbit anti-β-endorphin antiserum produced no change in either baseline serum prolactin or in the rise induced by swimming for 15 minutes at 20 C. Naloxone, 0.5 mg/kg intravenously, produced a small but statistically significant lowering of baseline serum prolactin levels, as well as a mild blunting of the stress-induced serum prolactin rise. The failure of anti- - endorphin antiserum to affect serum prolactin may be explained either by failure of the antiserum to gain access to hypothalamic prolactin regulating loci, or to lack of involvement of β-endorphin in the control of serum prolactin. The suppression of prolactin secretion seen with naloxone indicates that endogeneous opioids are involved in prolactin regulation, though the relatively small magnitude of the changes observed suggests that their role under physiological conditions may be a minor one.

Physiological evidence for the existence of prolactin releasing factor: stress-induced prolactin secretion is not linked to dopaminergic receptors.

Experiments were undertaken to demonstrate the existence of a physiological role of prolactin releasing factor (PRF). Hypothalamic control of prolactin secretion is achieved by secretion of prolactin inhibiting factor (PIF) and/or PRF. Since the putative PIF is dopamine, complete blockage of the dopaminergic PIF receptors should permit demonstration of PRF activity. The changes in prolactin concentration were monitored by taking a blood sample every 2 min through an indwelling atrial cannula. An excessive amount of pimozide (3 mg/kg) was used to block dopaminergic receptors and prolactin concentration was elevated as a result. This higher concentration of circulating prolactin was maintained for more than 30 h after a bolus injection of pimozide. In this situation, lacking functional dopaminergic PIF receptors, there were fluctuations in the circulating prolactin concentration throughout the experiment. If, after pimozide administration, rats were exposed to an acute (ether) stress, the stress consistently elevated the circulating prolactin concentration. Since there are no functional dopaminergic PIF receptors available under these conditions, a dopaminergic PIF cannot be involved in producing the prolactin surge induced by the acute stress. Therefore, these results suggest that a physiological PRF is involved in the generation of this prolactin surge, through the evidence is not direct.