Rise In Plasma PRL Research Articles

The Preovulatory Prolactin Surge Is Prolonged by a Progesterone-Dependent Dopaminergic Mechanism*

The preovulatory PRL surge consists of a sharp peak, a prolonged plateau, and a termination phase. This study examined the role of progesterone in maintaining elevated PRL release during the plateau phase and its effect on dopaminergic (DA) neuronal activity. Immature rats were injected with PMSG on day 28, and blood was collected during the periovulatory period. Plasma estradiol levels were elevated before and during the PRL peak and declined during the plateau. Plasma progesterone levels were low before and during the peak, rose 4- to 5-fold during the plateau, and decreased to basal levels at the termination phase. In a second experiment rats were subjected to acute ovariectomy (OVEX) or sham surgery (SHAM) just before the onset of the PRL surge. Some OVEX rats were either immediately implanted with an estradiol-containing capsule or given three injections of progesterone during the time of the plateau phase. Blood PRL levels in SHAM rats showed the typical peak, plateau, and termination phases. The PRL peak was evident, but the plateau was missing in OVEX rats with or without estradiol treatment. Replacement with progesterone restored the plateau. In a third experiment, the stalk-median eminence, posterior pituitary, and striatum were removed during the time of the midplateau phase. Tyrosine hydroxylase activity was determined in tissue homogenates by a coupled hydroxylation-decarboxylation assay. Tyrosine hydroxylase activity in the stalk-median eminence of SHAM and progesterone-treated OVEX rats was similar, but was significantly lower than that in OVEX rats with or without estradiol. Tyrosine hydroxylase activity in the posterior pituitary and striatum was unchanged. To assess the functional DA input to the anterior pituitary, haloperidol, a DA antagonist, was injected during the midplateau phase. It induced a 12- to 17-fold rise in plasma PRL in both untreated and estradiol-treated OVEX rats, but failed to increase PRL above the plateau levels in SHAM and progesterone-treated OVEX rats. We conclude that the plateau phase of the preovulatory PRL surge is dependent on the concomitant rise in progesterone. Progesterone probably acts by reducing the DA neuronal activity in the SME, resulting in an absence of functional DA input to anterior pituitary lactotrophs.

The effect of calcitonin on growth hormone secretion in acromegaly.

To determine whether human calcitonin inhibits GH secretion in acromegaly, as previously described for healthy subjects, the effect of an i.v. bolus injection of calcitonin or saline on GH levels in patients with active acromegaly was studied and compared to that of an i.v. bolus injection of the synthetic somatostatin analogue, octreotide. After the injection of calcitonin, GH levels decreased by 46% of initial values, whereas octreotide reduced GH levels by 87% and saline had no significant effect. Administration of calcitonin to acromegalics did not cause the transient rise in plasma PRL and TSH levels seen in normal subjects. Octreotide induced a decrease in plasma PRL in three out of seven patients. It is concluded that human calcitonin suppresses GH secretion in acromegaly, but not to normal levels; moreover the effect is less than that found for octreotide. In addition, acromegalic patients did not exhibit the PRL and TSH-releasing activity of calcitonin found in normal subjects, while octreotide inhibited PRL secretion in some acromegalic patients.

Time-Dependent Increase in Plasma Prolactin after Pituitary Stalk Section: Role of Posterior Pituitary Dopamine*

PRL secretion is inhibited by dopamine (DA) input from two systems: the tuberoinfundibular (TIDA) with terminals in the median eminence, and the tuberohypophyseal (THDA) with terminals in the posterior pituitary. The aims of this study were 1) to determine the effects of pituitary stalk section (SS), which prevents DA input from the TIDA neurons, on PRL release, and 2) to assess if the anterior pituitary receives any DA input after SS. Ovariectomized rats were subjected to SS or sham surgery. Jugular blood was collected on the day of surgery (day 0) and for 6 days thereafter and was analyzed for PRL by RIA. DA concentration in the posterior pituitary was determined by HPLC. Unexpectedly, SS caused only a 2- to 3-fold initial rise in plasma PRL on day 0. This was followed by a gradual rise to 4-, 6-, and 8-fold above control levels on days 2, 4, and 6, respectively, without a further increase by 2 weeks. During this time, DA concentrations in the posterior pituitary progressively declined to 66%, 28%, and 6% of control values on days 1, 2, and 6 after SS, respectively. In the second experiment, intact and SS rats were treated with the DA receptor antagonist haloperidol. Haloperidol induced a dramatic 30- to 40-fold increase in plasma PRL in intact rats. Haloperidol induced a 3-fold rise in plasma PRL on day 1 after SS and a transient 2.5-fold rise on day 2. On day 6 after SS, when DA in the posterior pituitary was barely detectable, haloperidol failed to increase PRL secretion. The DA agonist apomorphine caused similar inhibitions of PRL release on days 1 and 6 after SS. Injections of TRH stimulated PRL secretion equally well in intact and SS rats. We conclude that SS does not induce refractoriness to PRL secretagogues or a dysfunction of the anterior pituitary DA receptors. The immediate rise in PRL after SS is modest because the anterior pituitary still receives DA input from the posterior pituitary. A gradual exhaustion of posterior pituitary DA, caused by the disconnection of the THDA terminals from their perikarya, leads to the progressive rise in plasma PRL levels. The DA input affecting PRL release is derived exclusively from the TIDA and THDA neurons, but their relative contributions are yet unknown.

The Peak Phase of the Proestrous Prolactin Surge Is Blocked by Either Posterior Pituitary Lobectomy or Antisera to Vasoactive Intestinal Peptide*

The proestrous surge of PRL could result from a decrease in dopamine, an increase in PRL-releasing factor (PRF) or both. The objectives were to determine whether PRF from the posterior pituitary regulates the proestrous PRL surge, and to examine if there are interactions between PRF and vasoactive intestinal peptide (VIP). Posterior pituitary lobectomy (LOBEX) and passive immunization against VIP were employed. Adult cycling rats were subjected at 0900 h on proestrus to LOBEX or sham surgery (SHAM) under short term anesthesia, and were injected iv at 1330 h with 0.75 ml anti-VIP serum or normal rabbit serum. Jugular blood was collected hourly from 1400-2300 h and analyzed for PRL and LH by RIA. Oviductal ova were examined on estrus. The rise in plasma PRL in normal rabbit serum-treated SHAM rats was biphasic, with an early peak between 1500-1700 h and a lower plateau between 1900-2100 h. This rise was similar in profile and magnitude to that seen in intact rats. In contrast, LOBEX significantly attenuated the early peak, but did not alter the plateau. Passive immunization against VIP of either SHAM or LOBEX rats mimicked the effect of LOBEX alone on PRL release. Neither surgery nor anti-VIP serum affected the profile of the LH surge which was sharp and symmetrical, and all rats ovulated with 15-16 ova per rat. To determine whether VIP is the posterior pituitary PRF, selected tissues removed on proestrus or diestrus-1 were analyzed for VIP by RIA. VIP was undetectable (less than 20 pg/organ) in the posterior pituitary on either day examined. The contents of VIP in the anterior pituitary, medial basal hypothalamus, and paraventricular nuclei were unchanged between diestrus-1 and proestrus. The proestrous surge of PRL consists of two components: an early peak and a late plateau. The peak phase appears to be dependent on PRF input from the posterior pituitary. This input might be regulated by VIP, and interactions between the two could occur at the level of the hypothalamus, anterior pituitary, or both. The plateau phase of the PRL surge is independent of the posterior pituitary and VIP, and might involve hypothalamic dopamine.

The interaction of growth hormone releasing hormone with other hypothalamic hormones on the release of anterior pituitary hormones.

To determine whether the 29 amino-acid fragment of growth hormone releasing hormone (GHRH) can be combined with other hypothalamic releasing hormones in a single test of anterior pituitary reserve, the responses of anterior pituitary hormones to combinations of an i.v. bolus of GHRH(1-29)NH2 or saline with an i.v. bolus of either LH releasing hormone (LHRH) plus TRH, ovine CRH(oCRH) or saline were studied. Each infusion of GHRH(1-29)NH2 resulted in a rapid increment of the plasma GH value. Infusion of GHRH(1-29)NH2 also caused a small and transient rise in plasma PRL, but no change in the integrated PRL response. The combination of GHRH(1-29)NH2 with LHRH plus TRH caused a larger increment of peak and integrated plasma TSH levels than LHRH plus TRH alone. GHRH(1-29)NH2 did not affect the release of other anterior pituitary hormones after infusion with oCRH or LHRH plus TRH. Because of the finding of potentiation of the TSH-releasing activity of LHRH plus TRH by GHRH(1-29)NH2, the study was extended to the investigation of TSH release after infusion of TRH in combination with either GHRH(1-29)NH2 or GHRH(1-40). In this study the combination of TRH with both GHRH preparations also caused a larger increment of the peak and integrated plasma TSH levels than TRH alone. It is concluded that GHRH(1-29)NH2 possesses moderate PRL-releasing activity apart from GH-releasing activity. In addition, GHRH potentiates the TSH-releasing activity of TRH.(ABSTRACT TRUNCATED AT 250 WORDS)

Persistence of a defective tuberoinfundibular dopaminergic function in rats after long-term removal of oestrogen treatment. An in vivo study.

The function of the tuberoinfundibular dopaminergic (TIDA) neurons of 49 rats bearing oestradiol-valerate (EV)-induced prolactin (Prl) secreting tumours (prolactinomas) was evaluated in vivo, 7 months after discontinuation of EV-treatment, with neuroactive drugs acting via stimulation or inhibition of DA neurotransmission. Based on the size and morphologic appearance of the pituitary and on determination of plasma Prl levels, rats previously treated with EV could be divided into those bearing macro- (31/49) and those bearing micro-prolactinomas (18/49). Administration of the indirect DA agonist drug nomifensine (10 mg/kg iv) lowered plasma Prl levels in control rats, but failed to do so in rats bearing either macro- or microprolactinomas. Administration of the DA receptor antagonist domperidone (50 micrograms/kg ip) or the synthetic enkephalin analogue FK 33-824 (1 mg/kg ip) failed to induce a rise in plasma Prl in rats with macro-, but induced a clear-cut rise in plasma Prl in those with microprolactinomas. Prl unresponsiveness to all three neuroactive drugs indicates that long time after EV withdrawal TIDA neuronal function is still highly impaired in rats bearing EV-induced macroprolactinomas. The impairment of TIDA neuronal function would be of lesser extent in rats bearing microprolactinomas as revealed by a defective response to only one of the three applied neuroendocrine probes.

Plasma prolactin in the rat during suckling without prior separation from pups.

The relation between suckling and plasma prolactin (Prl) was studied in the rat, without prior separation of the dam from its pups. When the pups were replaced by a hungry foster litter, upon renewed suckling plasma Prl showed episodic increases and decreases in individual rats. When, subsequent to litter removal, similar rats were injected with perphenazine, a significant increase of plasma Prl was observed. This indicates that a decline of plasma Prl during suckling was not caused by exhaustion of Prl stores in the pituitary. In 22 individual rats blood was sampled every other minute while observations were made on nursing behaviour of the dams. During apparent suckling, increases as well as decreases of plasma Prl occurred. However, in most cases suckling did not affect plasma Prl, i.e. it remained stable at a high or a relatively low level. On the other hand, a considerable rise of plasma Prl was frequently observed when a dam was away from the nest. The data indicate that in the physiological situation Prl secretion from the pituitary is not directly related suckling activity, though episodes of suckling are essential to maintain a high Prl secretory capacity of the pituitary gland.

Stress-induced secretion of adrenocorticotropin in rats is inhibited by administration of antisera to ovine corticotropin-releasing factor and vasopressin.

Intact handled rats were pretreated with the immunoglobulin G fractions from normal rabbit serum or antisera to ovine corticotropin-releasing factor (CRF) and/or vasopressin and subjected to restraint or formalin stress. The formalin-induced rise in plasma ACTH was reduced to 28% in rats pretreated with anti-CRF, to 53% in those pretreated with antivasopressin, and to 16% in rats given both antibodies. Pretreatment of animals with anti-CRF, antivasopressin, or a combination of both antibodies also attenuated the ACTH response to restraint stress to 13%, 37%, and 12%, respectively, of those in normal rabbit serum-treated rats. Antiserum pretreatment did not reduce the restraint- or formalin-induced rise in plasma PRL in the same animals, however. We conclude, therefore, that both vasopressin and an ovine CRF-like peptide are physiologically relevant peptides involved in stress-induced ACTH release.

Inhibitory effect of cimetidine on L-dopa-stimulated growth hormone release in normal man.

Some evidence suggests the existence of a histaminergic influence on GH secretion in animals and man. We used cimetidine, a specific H2-receptor antagonist, to study the possible interference of H2-receptor blockade on plasma GH release by L-dopa and on PRL inhibition by L-dopa in normal man. Seven healthy normal male volunteers aged 23-36 years received a single oral dose of L-dopa (500 mg) or an i.v. bolus of cimetidine (300 mg) or both (L-dopa 30 min before cimetidine). Blood samples were taken at various times over 2 h and plasma GH and PRL levels measured. Cimetidine alone did not alter basal plasma GH values; L-dopa elicited the well-known GH releasing effect with peak values at 75 min (15.65 +/- 2.8 ng/ml); cimetidine injected 30 min after L-dopa ingestion significantly blunted the GH response to L-dopa and peak values (4.7 +/- 1.6 ng/ml) were delayed to 105 min. Cimetidine provoked a rapid rise in plasma PRL with the peak value of 15 +/- 3 ng/ml at 15 min, followed by a return to near basal values in 90-120 min. L-Dopa completely inhibited the PRL response to cimetidine. We conclude that there is an inhibitory influence of the H2-receptor antagonist cimetidine on GH release by L-dopa. This, together with the action of cimetidine on PRL secretion (with or without L-dopa), suggests a possible antidopaminergic effect of H2-receptor blockade at the level of the central nervous system.

Effects of human pancreatic tumor growth hormone-releasing hormone (hpGRH1-44-NH2) on immunoreactive and bioactive plasma growth hormone in normal young men.

Synthetic human pancreatic tumor GH-releasing hormone (hpGRH 1-44-NH2) was given by iv bolus injection to 10 normal men at doses of 75, 150, 300, and 600 micrograms. At all doses the plasma GH responses were similar in an individual subject. Among subjects, however, the responses were significantly different, with peak GH concentrations ranging between 9.0 micrograms/liter and 54.9 micrograms/liter. The GH released in response to GRH was bioactive in the Nb2 lymphoma cell multiplication assay. The circulating GH 30 and 60 min after GRH was detected in 3 molecular forms corresponding to little, big, and big-big GH. These forms averaged 50%, 30%, and 20% of the total immunoreactive GH, respectively. The mean rise of plasma somatomedin-C, from 1.86 U/ml to 2.21 U/ml 24 h after GRH, was not statistically significant. A small but statistically significant GRH dose-dependent rise in plasma PRL (mean PRL concentrations 10 min after 600 micrograms GRH, 11.13 micrograms/liter occurred consistently after GRH injection. The evidence that the GH released by GRH is bioactive supports the potential use of GRH for therapeutic applications.

Opiate modulation of the anterior pituitary hormone response during suckling in the rat.

We have investigated the influence of endogenous opiates on hormone responses during suckling in the rat. In complementary experiments, opiate receptors were blocked by naloxone (NAL) or endogenous opiate release from the pituitary was inhibited by dexamethasone (DEX). Serial blood samples from unanesthetized suckled rats were then assayed for plasma PRL, beta-endorphin-like immunoreactivity (beta-END-LI), TSH, and GH levels. Identical studies were also done in saline-treated (control) suckled rats and in unsuckled rats exposed to control objects. Whereas suckling caused a rise in plasma PRL, beta-END-LI, and GH, introduction of plastic control objects did not elevate hormone levels. NAL blocked the GH rise and depressed TSH levels, but did not significantly inhibit the PRL or beta-END-LI response. DEX prevented the beta-END-LI rise and blocked the GH rise, but did not inhibit TSH. DEX enhanced PRL release during suckling. These results demonstrate that 1) the responses of beta-END-LI, PRL, and GH are not an artifact of the sampling procedure; 2) PRL release during suckling is independent of beta-END-LI release by the pituitary; and 3) suckling stimulates the release of ACTH, beta-END, and beta-lipotropin from the anterior pituitary. Our results are consistent with both a role of pituitary beta-END in the control of GH and a role of corticosterone in the control of PRL during suckling.

Release of oxytocin and prolactin by suckling in rabbits throughout lactation.

Plasma oxytocin and PRL were measured in serial samples of blood collected from lactating rabbits nursing five to seven (mean, six) young on a once-daily suckling regimen. Each suckling episode lasted 4.0 +/- 1.1 (+/- SD) min on the average. Samples were obtained by means of an indwelling cardiac catheter before and 1, 3, 5, 10, 20, 30, and 60 min after suckling began. Measurements were performed at several stages of early, mid-, and late lactation. Oxytocin levels rose to peak values during suckling and declined rapidly after suckling stopped. PRL levels, on the other hand, did not reach peak values until 1-5 min after suckling had stopped, at which time plasma PRL concentrations plateaued and, in early and midlactation, were sustained at peak levels for 2-3 h; in late lactation, PRL secretion was not sustained after suckling had ceased. Peak PRL levels were relatively constant throughout most of lactation, with no significant differences between groups until late in lactation, when peak levels fell rather abruptly from a mean of 74 +/- 33.5 to 10.5 +/- 13.3 (+/- SD) ng/ml around day 25 in spite of a constant number of young and constant suckling frequency. Suckling failed to elicit any PRL release on day 30, but the administration of fluphenazine, a dopamine antagonist, did cause a rise in plasma PRL. Oxytocin release increased with advancing lactation, rising, on the average, 40 pg/ml on day 2 and to 250 and 490 pg/ml in mid- and late lactation, respectively. Dopaminergic agonist and antagonist drugs given to the doe before the nursing episode did not influence oxytocin release in response to suckling. Without a rise in plasma oxytocin, the young obtained no milk, but above a threshold level, there was no significant correlation between peak oxytocin levels and milk yield. When suckling failed to induce PRL secretion, milk secretion ceased rapidly in spite of copious oxytocin secretion. The failure of suckling to induce PRL release in late lactation, therefore, appears to be an important factor in the cessation of lactation.

Relationship of prolactin release in lactating rats to milk ejection, sleep state, and ultrasonic vocalization by the pups.

PRL release, milk ejection, and electroencephalographic states of sleep were monitored in conscious, lactating Holtzman rats. Plasma PRL levels were low in rats separated from their litters, but they increased when pups were returned to the cage, attached to the nipples of the mother, and suckled. The pups emitted ultrasonic vocalizations upon their return to the cage and before their attachment to the nipples. Exposure of mothers to the vocalizations of pups, whereas nipple attachment was prevented, failed to increase PRL release. In confirmation of previous work, milk ejection did not occur until the suckled mother exhibited electroencephalographic signs of sleep, and milk ejection could be inhibited if sleep was prevented. In contrast, sleep was not a prerequisite for PRL release and sleep deprivation of suckled mothers could not inhibit release of PRL. In summary, suckling-induced release of PRL was followed by an increased incidence of sleep and then by milk ejection. It is hypothesized that the rise in plasma PRL induces the sleep necessary for the reflex release of oxytocin required for milk ejection.

Defective regulation of prolactin secretion after successful removal of prolactinomas.

The PRL response to nomifensine (Nom), an indirect DA agonist; domperidone (Dom), a DA receptor antagonist; and TRH, which directly stimulates the PRL-secreting cells, was evaluated 2-53 months after surgery in 13 patients in whom successful removal of a prolactinoma had resulted in normal serum PRL levels and return of regular menses or libido and potency. In addition, the pattern of TSH secretion in response to Dom and the spontaneous rise in plasma PRL of 6 cured patients during pregnancy were evaluated. Nom induced an inconsistent decrease in basal PRL levels, a pattern contrasting with that in healthy women in whom plasma PRL was markedly suppressed after administration of the drug. Dom and TRH elicited a significant rise of basal PRL levels, but the rise was markedly lower than that occurring in the control group. The TSH increment after Dom treatment was lower than that before surgery, though higher than that in the controls. Evaluation of individual patients showed that only one patient had a normal PRL response to either Nom or Dom, while the TSH response to the latter returned to normal in five of seven patients. During pregnancy, plasma PRL rose inconsistently in the patients, and PRL levels were generally lower than those in normal pregnant women. These results suggest the presence of an abnormality in the dopaminergic mechanism(s) of PRL control before and after adenomectomy or, less likely, the existence of impaired pituitary function or reserve.

Evidence that the dopaminergic prolactin-inhibiting factor mechanism regulates only the depletion-transformation phase and not the release phase of prolactin secretion during suckling in the rat.

We have compared the effectiveness of stalk-median eminence (SME) extracts, dopamine, and bromocriptine (CB-154) in inhibiting the release of PRL into the plasma during suckling when injected before depletion with that when the injections were given after the pituitary stores of PRL had been depleted and transformed by 10 min of suckling. We found that a single injection of either neutralized acidic extracts of SME at a dose of one or two SME equivalents per rat or 625 ng dopamine effectively prevented both the depletion of PRL within the pituitary and the subsequent rise in plasma PRL when given 1-3 min before the onset of suckling. Likewise, a single injection of bromocriptine (0.5 mg) given 20-30 min before the onset of suckling totally blocked pituitary depletion and the subsequent release of PRL into the circulation. However, the PRL concentration rose normally in the plasma in response to suckling when either SME extract or bromocriptine was given after PRL depletion had first been effected by prior short term (10 min) suckling. These data indicate that the depletion-transformation phase but not the release phase (into the circulation) of PRL secretion is under inhibitory control by a dopaminergic PRL-inhibiting factor system.

Plasma prolactin increase following electric stimulation of the amygdala in humans.

Plasma levels of PRL, GH, FSH, LH, and TSH were studied at various intervals after electric stimulation of the amygdala, in 5 patients in whom electrodes had been chronically implanted in the course of their evaluation for surgical treatment of uncontrollable, temporal lobe seizures. Electric stimulation, but not sham stimulation, elicited in all cases a significant rise in plasma PRL. Plasma GH rose only in 1 patient and TSH in another. No significant changes in plasma FSH or LH were detected. It is suggested that a fine control mechanism of the hypothalamic hypophyseal final common pathway for the control of PRL secretion, may be mediated either by the ventral amygdalohypothalamic pathway or via the stria terminalis.

Dual gamma-aminobutyric acid control of prolactin secretion in the rat.

Contrasting data have been reported so far on the role played by γ-aminobutyric acid (GABA) in the control of PRL secretion in the rat. Based on the findings that systemic administration of muscimol (M), a powerful agonist at GABA receptors, lowered plasma PRL in male rats, studies were undertaken to determine both the mechanism (s) of M-induced inhibition of plasma PRL and the reason (s) for the disparity between data pointing to a stimulatory and those favoring an inhibitory role of GABA on PRL secretion. In freely behaving male rats, administration of either picrotoxin (PICRO; 1 mg/kg, iv) or bicuculline (BIC; 0.4 mg/kg, iv), two GABA antagonist drugs, failed to counteract and instead potentiated the PRL-lowering effect of M (2.0 mg/kg, iv). BIC alone decreased baseline PRL levels. In ovariectomized estrogenprimed rats, PICRO and BIC, at the same doses, elicited a striking decline of the elevated basal PRL levels and were again unable to oppose the effect of M. In contrast to its effect after systemic injection, M (500 ng) injected into the lateral ventricle of freely behaving male rats elicited a clear-cut rise in plasma PRL which was suppressed by BIC. The dual effect of M on PRL secretion according to the route of administration was indicative of an extra-central nervous system site of action of the drug when given systemically. In keeping with this hypothesis, M (2.5 × 10-5 M) inhibited PRL release from rat isolated anterior pituitaries (AP), an effect which was abolished by coincubation with equimolar doses of PICRO; however, M (2 mg/kg, iv) failed to lower plasma PRL levels in hypophysectomized rats bearing an ectopic AP. Also favoring a direct AP site of action for M was the observation that it completely abolished, after systemic administration (2 mg/kg, iv), the striking rise in plasma PRL exerted by a-methylparatyrosine, a drug which acts at the central nervous system level. Collectively, these data would demonstrate the existence of a dual GABAergic control of PRL secretion, one stimulatory, exerted through the central nervous system, and the other inhibitory, occurring at the level of the AP.

Involvement of Brain Serotonin in the Prolactin- Releasing Effect of Opioid Peptides*

The role played by brain serotonin (5-HT) neurotransmission in mediating the PRL-releasing effect of enkephalins was investigated in the rat. Both MetG-enkephalin (Metenk) and (D-Met2, Pro5)-enkephalinamide (EKNH2), an analog with long lasting analgesic activity, were used in freely moving rats bearing a cannula chronically implanted into the jugular vein. Met-enk injected intracerebroventricularly (IVT; 200 and 400 μg/rat) induced a marked and dose-related increase in plasma PRL; EKNH2 (0.2 mg/kg, iv) induced a rise in plasma PRL similar to that evoked by Met-enk (400μg/rat). Metergoline (1 mg/kg, iv), a 5-HT receptor blocker, significantly reduced the PRL-releasing effect of Met-enk (200 μg/rat); these results were duplicated by using another 5-HT receptor blocker, i.e. methysergide (2.5 mg/kg, iv). Metergoline and methysergide also significantly reduced the increase in plasma PRL due to EKNH2. 5,6-Dihydroxytryptamine (50 μg, IVT), a neurotoxic drug which destroys 5-HT nerve terminals, almost completely abolished the rise in plasma PRL induced by EKNH2 (1.0 mg/kg, ip). However, blockade of 5-HT biosynthesis by p-chlorophenylalanine (100 mg/kg, sc, twice) potentiated the rise in plasma PRL induced by EKNH2, an effect possibly resulting from the development of supersensitive 5-HT receptors. Pretreatment with quipazine (15 mg/kg, iv), a direct stimulant of 5-HT receptors, almost completely suppressed the PRL-releasing effect of Met-enk (400 µg/ rat), EKNH2, and IVT injected 5-HT (2 μg/rat). Blockade of catecholamine neurotransmission by a-methyl-p-tyrosine (200 mg/kg, ip) did not modify the PRL-releasing effect of EKNH2. In all, these results suggest that enkephalins exert their PRLreleasing effect via mediation of the brain 5-HT system.

Effects of Indoleamines and Their Newly Identified Metabolites on Prolactin Release in Rats*

Plasma immunoreactive PRL responses to indoleamines and their metabolites were studied in urethane-anesthetized rats. All drugs were injected into the lateral ventricle and blood samples were serially collected from a jugular vein. Serotonin and melatonin caused a significant increase in plasma PRL with peak values at 10-20 min after the injection. Significant increase in plasma PRL were also observed after the administration of 5-hydroxykynurenamine (5-HK), a newly identified serotonin metabolite. The potency of 5-HK was less than that of serotonin but much greater than that of melatonin. In contrast, plasma PRL did not change significantly in response to N-acetyl-5-methoxykynurenamine, another newly identified metabolite of melatonin, or a vehicle solution. Simultaneous administration of melatonin significantly blunted the plasma PRL response to serotonin, whereas the rise in plasma PRL induced by 5-HK was not blunted by melatonin. These results suggest that indoleamines as well as their metabolites play a role in regulating PRL secretion in rats.

Stimulation of rat prolactin secretion in vivo by arginine vasotocin: influence of age of solution, nighttime administration, and dose.

In male rats pretreated for 3 days with 50 microgram of estradiol benzoate (E) and 25 mg of progesterone (P), the i.v. administration of 1 microgram of arginine vasotocin (AVT) from solutions that were 0, 6, 24 or 48 h old caused a significant rise in plasma prolactin (Prl) 10 min after injection. In the 2nd experiment, the i.v. injection of 1 microgram AVT into EP-primed adult male rats at either 01:00 (during darkness) or 13:00 h (during light) resulted in a significant and similar elevation in plasma Prl levels. In the 3rd experiment, normal adult male rats under urethane anaesthesia were given an i.v. injection of diluent or of 100 ng, 1 microgram or 10 microgram AVT. A significant rise in plasma Prl was observed at 10 and 20 min following injection only in the group treated with 1 microgram AVT. In none of these experiments did AVT alter the content of pituitary Prl.