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Endocrinology Vol. 142, No. 6 2296-2302
Copyright © 2001 by The Endocrine Society

ARTICLES

Control of the Estradiol-Induced Prolactin Surge by the Suprachiasmatic Nucleus

Inge F. Palm, Eline M. van der Beek, Hans J. M. Swarts, Jan van der Vliet, Victor M. Wiegant, Ruud M. Buijs and Andries Kalsbeek

Netherlands Institute for Brain Research (I.F.P., J.v.d.V., R.M.B., A.K.), 1105 AZ Amsterdam, The Netherlands; Human and Animal Physiology Group (I.F.P., E.M.v.d.B., H.J.M.S.), Department of Animal Sciences, Wageningen University, Wageningen 6709 PJ, The Netherlands; and Medical Pharmacology Group (V.M.W.), Rudolf Magnus Institute for Neurosciences, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands

Address all correspondence and requests for reprints to: I. F. Palm, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands. E-mail: I.Palm{at}nih.knaw.nl


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In the present study we investigated how the suprachiasmatic nucleus (SCN) controls the E2-induced PRL surge in female rats. First, the role of vasopressin (VP), a SCN transmitter present in medial preoptic area (MPO) projections and rhythmically released by SCN neurons, as a circadian signal for the E2-induced PRL surge was investigated. Using a reverse microdialysis technique, VP was administered in the MPO during the PRL surge, resulting in a suppression of the surge. VP administration before the surge did not affect PRL secretion. Also, administration of a V1a receptor antagonist before the surge was ineffective. Second, lesions of the SCN were made that resulted in constant basal PRL levels, suggesting that with removal of the SCN a stimulatory factor for PRL secretion disappeared. Indeed, the PRL secretory response to blockade of pituitary dopamine receptors was significantly reduced in SCN-lesioned animals. These data suggest that the afternoon decrease of VP release in the MPO by SCN terminals enables the PRL surge to occur, and may thus be a circadian signal for the PRL surge. Simultaneously the SCN is involved in the regulation of the secretory capacity of the pituitary, possibly via specific PRL-releasing factors.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
FEMALE RATS exhibit a preovulatory PRL surge, occurring on proestrus afternoon, concomitant with the surge in LH (1, 2). PRL secretion is regulated by a combination of inhibiting and stimulating compounds (for review see Ref. 3). The main inhibiting factor is dopamine (DA), produced by neurons in the periventricular-arcuate region. A decrease in DA-ergic activity in the afternoon has been shown to be a prerequisite for the initiation of a PRL surge (4, 5). However, the full amplitude of the PRL surge can only be explained by the additional activation of PRL-releasing factors (6, 7, 8).

The proestrus PRL surge is induced by positive feedback actions of E2 together with a circadian signal originating in the suprachiasmatic nucleus (SCN) (9, 10). E2 acts mainly in the medial preoptic area (MPO) (11), most likely via estrogen-receptor-containing neurons. In addition, lesion and electrical stimulation studies have demonstrated a role for the MPO in the regulation of the PRL surge (12, 13, 14). SCN control of the preovulatory PRL surge became evident by the fact that its occurrence is entrained to the environmental light-dark cycle or to the activity cycle in free-running, blinded rats. Estrus cycles and the PRL surge are suppressed by continuous light exposure and by lesions of the SCN (12, 15). Continuous exposure of ovariectomized (OVX) rats to high E2-levels results in daily PRL surges, which are eliminated by SCN lesions (16, 17).

The aim of the present study was to investigate further the mechanisms via which the SCN may regulate the PRL surge in OVX, E2-treated animals. It has been postulated and confirmed that the circadian release of SCN neurotransmitters in specific SCN target areas serves to convey circadian information to autonomic, behavioral, and hormonal systems (18). Thus circadian release of vasopressin (VP) in the dorsomedial hypothalamus was shown to be an inhibitory circadian signal that is partly responsible for the rhythm in corticosterone secretion (19, 20). SCN fibers that contain VP as a putative neurotransmitter terminate on the estrogen receptor neurons in the MPO (21, 22, 23, 24). Because the MPO is crucial for the regulation of the PRL surge (12, 13, 14) and the positive E2 feedback (11), we hypothesize that circadian release of VP in the MPO may be a circadian signal for the timing of the PRL surge. To study the effects of VP on PRL secretion, VP was administered into the MPO during different time windows by means of a reverse microdialysis technique. In addition, the role of endogenously released VP was investigated by administration of a V1a receptor antagonist at different times of the light/dark cycle. To establish whether the timing of the PRL surges (and thus possibly the functioning of the SCN) is unaltered in OVX, E2-treated rats, we included intact proestrus animals in the experiments.

The use of SCN lesions for the study of the circadian regulation of hormone release has proven to be useful. First, the disappearance of hormonal rhythms supports the crucial role for the SCN in generating these rhythms. Second, the hormone levels after lesioning may indicate the type of control the SCN exerts on hormone secretion. For example, the intermediate corticosterone levels observed in SCN-lesioned animals suggested that the SCN contains both inhibitory and stimulatory factors regulating the corticosterone rhythm, which was later confirmed (19, 20). Third, the effects of a specific transmitter may be expressed more clearly, because all other possibly interfering SCN influences are removed (for example, see Ref. 25). For these reasons SCN-lesioned animals were included to study the effects of VP on PRL secretion.

Based on the results from the experiments just described, which indicated a stimulatory role for the SCN in the regulation of PRL secretion, we performed an additional experiment. The DA-ergic inhibition of PRL secretion is strongly present; therefore, an eventual underlying stimulation of PRL secretion may not be detectable without removing the DA-ergic inhibition. The approach we used was based on a previous study, which used a peripherally acting DA antagonist, domperidone (DOM), to block the effects of DA on the secretion of PRL (6). In this way, the authors were able to demonstrate a diurnal variation in the PRL secretory response to DOM, which could be attributed to various putative PRL-releasing factors. Using the same approach we investigated the effects of SCN-lesions on the PRL secretory response to DOM in OVX, E2-treated rats. In addition, we measured plasma corticosterone levels as an indicator for possible stress-related effects on PRL release in all experiments (26, 27).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Female Wistar rats bred in our laboratory from HcdCpd:WU rats (Harlan, Zeist, The Netherlands) were housed under a regular 12-h light, 12-h dark schedule in a temperature controlled room with food and water available ad libitum. Animals were housed individually in clear plexiglass cages from 9 days prior to the microdialysis experiments until the end of the experiments. All surgeries were performed under Hypnorm [0.05 ml per 100 g body weight (BW), im] and Dormicum (0.04 ml per 100 g BW, sc) anesthesia. After waking up from anesthesia, animals received a sc injection of an analgetic (Temgesic, 0.03 ml per 100 g BW). All experimental procedures were approved by the local Animal Experimentation Committee of the Royal Netherlands Academy of Sciences.

Exp 1: comparison of the PRL surge in proestrus and OVX, E2-treated rats
To compare PRL surges in proestrus and OVX, E2-treated animals, blood sampling catheters were implanted through the right jugular vein in eight intact animals that showed at least two consecutive 4-day cycles as monitored by daily vaginal lavage. Surgery was performed on the day of diestrus I, proestrus, or estrus. Blood sampling commenced on the first proestrus day after the reestablishment of at least one 4-day cycle. Ten hourly blood samples were taken, starting at Zeitgeber time (ZT) 6.5 (ZT 0 = lights on).The PRL surge of proestrus animals was compared with the PRL surges of the control animals used for the microdialysis experiments. These animals were OVX for 2 weeks before receiving the blood sampling catheter, a microdialysis probe aimed at the left MPO and the E2 implant during a single surgical procedure, as described previously (25). Microdialysis experiments started a week after surgery, and animals dialyzed with Ringer solution (NaCl 9 g/liter, KCl 0.3 g/liter, CaCl 0.25 g/liter; control animals) were used for comparison with the proestrus animals.

Exp 2: role of VP in the MPO as a circadian signal for the PRL surge
To study the role of VP, acting in the MPO as a putative circadian signal for the PRL surge, VP (50 ng/µl dissolved in Ringer solution; Sigma, St. Louis, MO) was administered through a microdialysis probe during different time windows in separate groups of animals. The first period was from ZT 7.5 to 12.5, when endogenous VP levels are expected to decline (28), and blood sampling started just before the onset of VP administration, resulting in 8 hourly samples from ZT 7.5 to 14.5. The second period was from ZT 0 to 5 during the predicted increasing phase of the endogenous VP rhythm (28) and blood samples were taken at ZT 0, 1, and hourly from ZT 5.5 to 12.5. The amount of VP released into the brain by this method was reported to be 0.5% (29). [3H]VP administered via the same probe showed that about 0.1% of labeled VP passes the membrane to enter the brain (Wortel, J., and J. Van Heerikhuize, unpublished data). Therefore, the expected amount of VP released from the probe tip is estimated to be less than 50 pg/µl.

The role of endogenous VP was studied by administration of the V1a receptor antagonist Manning compound (d(CH2)5-[Tyr(Me2)]AVP; 10 or 25 ng/µl; Brunschwig Chemie, Amsterdam, The Netherlands). The V1aR antagonist was administrated from ZT 4 to 7, during the expected peak phase of the endogenous VP rhythm, and PRL was measured in hourly blood samples from ZT 3.5 to 12.5. In addition, the antagonist was administered from ZT 0 to 5. A single control group, receiving Ringer dialysis from ZT 0 to 5, was included because VP and V1a receptor antagonist dialysis from ZT 0 to 5 were performed during the same experiment.

Exp 3: effects of bilateral SCN lesions
Bilateral thermal lesions of the SCN were made and their effectiveness was checked as described previously (25). Animals showing arrhythmic water uptake and behavior were OVX 5–6 weeks after lesioning of the SCN. Two weeks after ovariectomy, animals were provided with a sc E2 implant, a blood sampling catheter, and a microdialysis probe, similar to the SCN-intact animals of Exp 2. Initially, 72 animals were lesioned for the microdialysis experiments, of which 23 remained for further surgeries and experiments. Animals were dialyzed with Ringer solution (controls) or VP from ZT 7.5 to 12.5 and blood samples were taken as described above.

Exp 4: role of the SCN in the stimulation of PRL secretion
To investigate whether the SCN may be involved in PRL secretion independent from the major inhibitory regulation by DA, we blocked pituitary DA receptors with a peripherally acting DA antagonist, DOM in OVX, E2-treated, SCN-intact and SCN-lesioned animals. SCN lesions were made and checked as in Exp 3 and, of the 24 animals lesioned, 8 were used in the experiments. After a control sample taken at ZT 4, DOM (200 µg/kg BW, ICN Biomedicals, Inc., Costa Mesa, CA) or saline was injected via the jugular vein catheter as described previously (6). Subsequent blood samples were taken at 15, 30, 45, 60, 120, 180, and 240 min after the injection. One week later the experiment was repeated, reversing the treatment of DOM or saline from the previous experiment. DOM was dissolved in 7% acetic acid and further diluted to 200 µg/ml in PBS (pH = 7.6). The saline consisted of the same solution, but without DOM.

Blood sampling
Blood samples of 100–170 µl were taken for measurement of PRL and corticosterone levels. In all OVX, E2-treated animals, a single sample of 400 µl was taken at the end of the experiment and replaced with the same volume of saline to determine E2 concentrations. Samples were collected in heparinized ice-chilled tubes and centrifuged at 3000 rpm for 15 min. Plasma was stored at -20 C until hormone determination.

Histology
Of all SCN-intact animals, brains were collected after decapitation under CO2/O2 suffocation. The exact location of the microdialysis probe was verified in 25 µm cryostat brain sections of the MPO. The extent of the SCN lesions was examined in fixed vibratome sections (40 µm) of the MPO and SCN as described elsewhere (25). Briefly, polyclonal rabbit antibodies against VP (Truus, 25-01-86; Netherlands Institute for Brain Research, Amsterdam, The Netherlands) and vasoactive intestinal polypeptide (VIP; Viper, 18-9-86; Netherlands Institute for Brain Research) were used in a dilution of 1:4000. Detection was performed with biotinylated goat-antirabbit IgG (1:400), followed by Avidin-Biotin Complex-Elite (1:800, Vector Laboratories, Inc., Burlingame, CA). The immunoreaction was visualized with 0.05% 3,3-diaminobenzidine (Sigma) with 0.03% H2O2 and 0.2% nickel ammonium sulfate. Lesions were considered incomplete when either VP or VIP immunoreactive cells or fibers were detected in the SCN area or SCN projection pathways. In addition, the exact location of the microdialysis probes was verified in sections of the MPO.

Hormone determination
PRL concentrations were determined by a double-antibody RIA, using the rPRL-I-9 for labeling (obtained from the NIDDK, Bethesda, MD), anti-rPRL-s-415 as antiserum (obtained from Dr. H. G. Kwa, The Netherlands Cancer Institute, Amsterdam, The Netherlands) and with Sac-cel (donkey antirabbit; Welcome Reagents, Beckenham, UK) as a second antibody. The concentration of PRL is expressed relative to the rPRL-RP-3 reference. The assay sensitivity was 1.7 ng/ml at 90% bound ratio relative to the zero standard (B/Bo) and interassay and intraassay variations amounted to 15 and 7%, respectively. E2 was determined with a RIA kit (Diagnostic Products Corp.) following extraction of the plasma with dichloromethane. Concentrations are expressed relative to the kit reference with a sensitivity of 6 pg/ml at 90% B/Bo. The interassay and intraassay variations were 13.7 and 14.7%, respectively. Another RIA kit (ICN Biomedicals, Inc.) was used for corticosterone determination. Concentrations are expressed relative to the kit reference with a sensitivity of 8 ng/ml at 90% B/Bo. The interassay and intraassay variations of the kit were 6.9 and 7.2%, respectively.

Data analysis
Mean ± SEM PRL and corticosterone concentrations were calculated for each time point. Effects of treatment and time and their interaction were evaluated using an ANOVA for repeated measures, followed by Tukey’s post hoc test when significant differences were indicated. For comparison of the PRL and corticosterone profiles between different Ringer-dialysis experiments, the ANOVA was performed including only the ZT 7.5–12.5, because these samples overlapped in all experiments. Possible relations between plasma PRL and corticosterone levels were investigated with Pearson’s correlation analysis. Effects were considered to be significant if P was less than 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Exp 1: comparison of the PRL surge in proestrus and OVX, E2-treated rats
All intact cycling females resumed regular cycles after surgery, although this took more time in animals operated on diestrus I (12.3 ± 0.5 days to first proestrus) than in animals operated on proestrus or estrus (4.8 ± 0.7 days to first proestrus). The PRL surges in OVX, E2-treated rats dialyzed with Ringer solution from ZT 7.5 to 12.5 appeared comparable to the proestrus surge in amplitude, timing, and duration (Fig. 1AGo), just as the corticosterone levels were comparable (Fig. 1BGo). However, PRL surges in animals dialyzed with Ringer solution from ZT 0 to 5 or 4 to 7 were significantly reduced compared with ZT 7.5–12.5 and to proestrus animals. Still, significant changes in PRL release over time occurred in these animals (F(9,144) = 9.65, P < 0.01), with higher PRL concentrations in the afternoon (P < 0.05), indicating that a PRL surge was still present albeit with a reduced amplitude (Fig. 2Go). PRL levels in the ZT 7.5–12.5 group were significantly higher compared with the other groups at ZT 8.5–10.5 and 12.5. A significant effect for treatment was detected for corticosterone levels in the three Ringer-treated groups (F(2,19) = 10.548, P < 0.01), but no effects for time or the interaction were detected. Post hoc analysis revealed that at ZT 11.5, corticosterone levels were significantly higher in the ZT 7.5–12.5 group compared with the ZT 0–5 group (Fig. 2BGo). No correlation between corticosterone and PRL levels was detected.



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  		Figure 1. Mean ± SEM PRL (A and C) and corticosterone (B and D) levels in intact animals (shaded areas in A and B) and in OVX, E2-treated animals. A and B, In SCN-intact animals, microdialysis with VP (•, n = 26) from ZT 7.5 to 12.5 significantly suppressed the PRL surge without affecting corticosterone levels. PRL and corticosterone levels in Ringer-treated animals ({circ}, n = 10) were comparable to proestrus levels (mean levels ± SEM, n = 8). C and D, In SCN-lesioned animals, VP administration (•, n = 9) did not affect either PRL or corticosterone secretion. Both PRL and corticosterone were at constant levels, reduced compared with SCN-intact rats ({circ}, n = 6). Black bar, Dark period; horizontal hatched bar, period of microdialysis with VP.

 


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  		Figure 2. Mean ± SEM PRL (A) and corticosterone (B) levels in SCN-intact, OVX, E2-treated animals receiving Ringer microdialysis from ZT 7.5 to 12.5 (•, n = 10), ZT 4–7 ({blacksquare}, n = 7), or ZT 0–5 ({blacktriangleup}, n = 5). PRL levels were significantly higher in the ZT 7.5–12.5 dialyzed animals (*, P < 0.05) compared with the ZT 0–5 and 4–7 groups. PRL levels still showed a surge-like release pattern in the latter two groups. Corticosterone levels tended to decrease with earlier microdialysis. Significant differences were detected at ZT 11.5, between the ZT 7.5–12.5 and ZT 0–5 groups (*, P < 0.03). Black bar, Dark period.

 
Exp 2: role of VP in the MPO as a circadian signal for the PRL surge
Microdialysis probes were located between the rostral anteroventral periventricular nucleus and the caudal medial preoptic nucleus according to the atlas of Swanson (plates 17–22) (30). Animals with probes that were placed within the third ventricle or caudal from the SCN were excluded from further analysis. Based on these criteria a total of 8 animals were excluded. Although in the remaining animals variation still existed in the localization of the probes, no correlation with PRL or corticosterone release was detected.

VP administration from ZT 7.5 to 12.5 in SCN-intact, OVX, E2-treated rats clearly suppressed the afternoon surge, as indicated by an overall effect of treatment (F(1,34) = 18.56, P < 0.01), time (F(7,238) = 2.195, P < 0.05), and their interaction (F(7,238) = 9.213, P < 0.01). Post hoc analysis indicated significantly lower PRL concentrations during the dialysis period from ZT 8.5 to 12.5 (P < 0.05; Fig. 1AGo). After the 5-h dialysis period, PRL concentrations returned to control levels. Corticosterone secretion was unaffected by VP treatment during this time window (Fig. 1BGo). VP administration from ZT 0–5 or V1aR antagonist administration from ZT 0–5 or 4–7 did not affect PRL surges or corticosterone levels. The hormone concentrations in these groups overlapped well with the levels in the Ringer-treated control groups that are shown in Fig. 2Go.

Exp 3: effect of bilateral SCN lesions
Of the 23 SCN-lesioned animals operated on, 15 remained for final analysis after checking histological incomplete lesions (7 animals) or misplaced microdialysis probes (1 animal). Lesioning of the SCN resulted in the complete absence of PRL surges and significantly reduced constant low PRL levels (Fig. 1CGo) and constant intermediate corticosterone levels (Fig. 1DGo). VP administration from ZT 7.5 to 12.5 did not affect PRL or corticosterone release in SCN-lesioned animals (Fig. 1Go, C and D).

Exp 4: role of the SCN in the stimulation of PRL secretion
Of the 8 SCN-lesioned animals used for this experiment, 1 was excluded because of a histologically incomplete lesion. The absence of a PRL surge onset was seen in the saline-treated SCN-lesioned animals, whereas saline-treated SCN-intact animals showed a clear increase in plasma PRL levels between ZT 7 and 8 (Fig. 3AGo). Although the ANOVA for repeated measures indicated an overall effect of time (F(7,168) = 24.85, P < 0.01), further analysis revealed that no significant changes over time occurred in the SCN-lesioned control group. At ZT 4, PRL levels were not significantly different between SCN-lesioned and -intact animals (SCN lesioned: 18.4 ± 6.7, SCN intact: 5.7 ± 2.4 ng/ml, P = 0.087), and neither were corticosterone levels (SCN lesioned: 63.9 ± 8.4 ng/ml, SCN intact: 34.9 ± 12.2 ng/ml, P = 0.061). Next to the just mentioned effect of time, the ANOVA for repeated measures revealed significant effects for treatment (F(3,24) = 19.36, P < 0.01) and the interaction time x treatment (F(21,168) = 14.35, P < 0.01) on PRL secretion. DOM administration resulted in a pronounced increase in PRL secretion in both SCN-lesioned and -intact animals, but the response was significantly higher in SCN-intact rats (Fig. 3AGo). The total amount of PRL released during the sampling period was significantly greater in DOM-treated control animals compared with SCN-lesioned animals, whereas no significant differences were observed between the saline-treated groups (Fig. 3AGo, inset). DOM administration did not affect corticosterone secretion, and no differences between SCN-intact and SCN-lesioned animals were observed.



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  		Figure 3. Mean ± SEM PRL (A) and corticosterone (B) levels in SCN-intact (circles, n = 7) and SCN-lesioned (triangles, n = 7) OVX, E2-treated animals. DOM-treatment (black symbols and bars) resulted in a significant PRL secretory response compared with saline-treatment (open symbols and bars) and this response was significantly higher in SCN-intact compared with SCN-lesioned animals (#, P < 0.05). Indeed the total amount of PRL released during the sampling period (inset in A) differed significantly between lesioned and intact rats after DOM treatment (1-way ANOVA; #, P < 0.05 compared with same treatment in SCN-lesioned rats; *, P < 0.05 compared with saline of same lesion groups). No significant differences were observed for corticosterone secretion.

 
Estradiol
The E2 implants used for the microdialysis experiments resulted in plasma E2 concentrations within the physiological range (39.6 ± 2.1 pg/ml). In Exp. 4, comparable physiological levels of plasma E2 were detected during both the first (31.6 ± 1.8 pg/ml) and second (32.5 ± 3.5 pg/ml) experiment. In all experiments, E2 concentrations showed some variation among animals, but did not correlate with PRL or corticosterone concentrations.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we show a clear time-dependent inhibitory effect of VP administration in the MPO on the E2-induced PRL surge; only when VP was dialyzed during the second half of the light period it suppressed the PRL surge. At the same time, corticosterone levels were not only comparable between Ringer- and VP-treated animals, but also comparable to proestrus levels. Thus, the decrease in PRL levels is not the result of a stress-induced response, because stress would also affect corticosterone secretion. However, the reduced PRL surges seen in animals dialyzed before ZT 7 were accompanied by lower corticosterone levels as well, although no significant correlations were detected between PRL and corticosterone levels. These results suggest that dialysis of the MPO per se affects the expression of the full PRL surge in a time-dependent manner, as well as the activity of the hypothalamus-pituitary-adrenal axis.

Inhibition of the PRL surge was observed only when VP was administered at the moment that endogenous VP secretion by SCN neurons decreases. The circadian release pattern of VP by SCN neurons shows a peak during the middle of the day, and starts to decrease from ZT 7 on resulting in minimal levels during the dark period (28). These results suggest that the decrease in endogenous VP levels in the MPO is a prerequisite for the occurrence of the PRL surge. VP administration from ZT 0–5 is without effect, likely because PRL secretion is then already suppressed by the increasing and peak endogenous VP levels.

A role for endogenous VP in the regulation of the PRL surge was not established. V1aR antagonist administration before the PRL surge onset (ZT 0–5 or 4–7) did not result in increased basal PRL levels or an advancement of the PRL surge. Because antagonist administration was performed unilaterally, it is possible that normal VP neurotransmission in the contralateral MPO was sufficient to inhibit PRL secretion and thus to prevent a rise in PRL. Indeed, a bilateral blockade of {gamma}-aminobutyric acid receptors is necessary to completely prevent {gamma}-aminobutyric acid-mediated inhibition of melatonin secretion (31). In addition, the antagonist used is very specific for the V1a receptor (32). Both V1a and V1b receptor gene expression was demonstrated in the MPO (33, 34). Based on our results we cannot exclude that the inhibitory effect of VP is mediated by the V1b receptor. Thus although the ability of VP to inhibit surge release of PRL via its action in the MPO is clearly demonstrated, we cannot conclude if and how endogenous VP is involved in PRL regulation.

The preovulatory PRL surge is the result of reduced inhibitory and increased stimulatory regulation (8). The major inhibitory factor is DA, whereas a variety of compounds have been implicated as physiological stimulatory factors. DA-ergic activity is controlled by the SCN and shows a circadian decrease in the afternoon, which is necessary for the induction of the PRL surge (4, 5, 35, 36). The inhibitory effect of VP administration in the MPO on PRL release is most likely mediated via DA (37), involving direct projections of the MPO to the DA-ergic neurons in the periventricular-arcuate region (38). This provides a second putative pathway for SCN control of DA-ergic activity, because DA-ergic neurons are also directly innervated by SCN fibers, with yet unknown neurotransmitter content (39).

To study whether the SCN provides solely an inhibitory control of PRL secretion, directly or indirectly via VP in the MPO, SCN-lesions were made. This results in a depletion of VP innervation of the MPO (21, 23, 40), and a concomitant reduction in DA-ergic activity which remains constant over the day (4). If DA would be the sole regulator of PRL secretion, SCN lesions would result in constant intermediate PRL levels. Complete lesions of the SCN in OVX, E2-treated rats resulted in constant low PRL levels, which at ZT 4 tended to be higher than normal basal PRL levels in SCN-intact animals. These data are in agreement with the constant low PRL levels reported by Mai et al. (4) and show that the SCN also provides a stimulatory signal for the PRL surge, in addition to its DA-mediated inhibitory control.

The stimulatory role of the SCN was further confirmed by the fact that the PRL secretory response to a peripheral blockade of DA receptors with DOM was diminished in SCN-lesioned animals compared with SCN-intact rats. These data suggest that the SCN is involved in the regulation of the capacity of the pituitary to release PRL. The smaller but significant response to DOM in lesioned animals probably reflects the intrinsic PRL releasing capacity of the pituitary. Indeed, pituitary stalk sections, lesions of the median eminence, or pituitary grafts in hypophysectomized rats result in an increase in PRL secretion, indicating the intrinsic capacity of lactotrophs to secrete PRL in a pulsatile fashion independent from hypothalamic control (41, 42, 43, 44). On the other hand, we cannot exclude the possibility that the observed effects are caused by an increase in DA receptor number in the pituitary caused by the SCN lesion. The dose of DOM may then have not been sufficient to block all DA-receptors in lesioned animals, thereby allowing some DA-ergic inhibition to remain and suppress PRL secretion. To our knowledge, it is currently unknown if SCN-lesions affect DA receptor expression in the pituitary.

In previous studies, treatment of OVX rats with the same dose of DOM revealed a diurnal rhythm in the magnitude of the secretory response, in which VIP, serotonin, and oxytocin (OT) play a role (6). Indeed, intracerebroventricular infusions of VIP or OT antisera decrease the amplitude of the PRL surge (45, 46), although the exact anatomical location of their action remains unknown. Also, the recently described inhibitory effect of a V1 antagonist on the proestrus PRL surge (47), is likely to be mediated by OT receptors, because the antagonist that was used is nonselective for the V1a, V1b, and OT receptors (32). The presence of a diurnal rhythm in the activity of OT neurons, VIP release, and serotonin turnover in the paraventricular nucleus of the hypothalamus (48, 49), and the role of VIP as an SCN neurotransmitter, suggest that the decrease in the PRL secretory response in SCN-lesioned animals is due to SCN regulation of these PRL-releasing factors.

In conclusion, we showed a clear, time-dependent, inhibitory role for VP in the regulation of the PRL surge, most likely via an MPO-mediated stimulation of DA release in the median eminence. We hypothesize that SCN control of the PRL surge consists of the circadian regulation of DA-ergic activity, via VP-ergic projections to the MPO or direct projections to DA-ergic neurons. In addition, our results strongly suggest a role for the SCN in the stimulation of PRL secretion as well, possibly via a rhythmic stimulation of specific PRL releasing factors in the hypothalamus.

Received October 23, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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