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Department of Physiology, School of Life Science, National Yang-Ming University, Taipei 11221, Taiwan
Address all correspondence and requests for reprints to: Jenn-Tser Pan, Ph.D., Mental Health Research Institute, The University of Michigan, 205 Zina Pitcher Place, Ann Arbor, Michigan 48109-0720.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Estrogen secreted from maturing follicles in the ovary has been shown to be the key factor for inducing the afternoon PRL surge (6, 7, 8). Eliminating its presence by ovariectomy or by antibody against estrogen blocks the PRL surge (6, 8). Though progesterone (P4) is not essential for the appearance of the PRL surge, its presence is able to advance and potentiate the surge in a time (3–4 h latent period)- and dose (0.25–8 mg/kg BW)-dependent manner (7). It has been shown that during the proestrous afternoon, there is also an increase in P4 secretion from the ovary (9, 10). That P4 secretion may prolong the preovulatory PRL surge in the immature 28-day female rats treated with PMSG (11). It is not clear, however, whether it plays a physiological role on the timing and amplitude of the PRL surge in the adult rats.
Like all other steroid hormones, P4 acts on specific receptors in the cell (12). Specific binding sites for P4, the P4 receptor (PR) itself, or its messenger RNAs (mRNAs) have been mapped in the brain using autoradiographic (13), immunohistochemical (14), or in situ hybridization methods (15), and they are found to distribute widely in the brain, especially within the hypothalamic areas. The dependence of PR expression on the presence of estrogen and its colocalization with estrogen receptor also are well known (14, 15, 16). All this evidence supports the notion that the proestrous rise of P4 may play an important role in the estrogen-induced afternoon PRL surge. Moreover, combined autoradiographic and immunohistochemical studies (17, 18) have shown that nearly 90% of the tyrosine hydroxylase (TH)-immunoreactive neurons in the hypothalamic arcuate nucleus contain PRs, which finding strongly suggests that the primary action of P4 may be through the TIDA neurons. In fact, several studies (11, 19, 20, 21, 22, 23) have reported a modulatory effect of P4 on dopamine synthesis and release from the hypothalamus but with variable results. Possible reasons are that various animal models and quantitative methods were used, and the sampling time points were varied because the diurnal nature of TIDA neuronal activity was not recognized.
In this study, we used OVX, OVX plus estrogen-treated, and intact female rats as animal models, and we determined the effect of P4 on the diurnal change of TIDA neuronal activity by measuring 3,4-dihydroxyphenylacetic acid (DOPAC) concentration in the median eminence (ME) and serum PRL, by RIA. The ME DOPAC level has been shown to be a reliable index for inferring the activity of DA neurons (24). The involvement of specific PR was determined by using a PR antagonist (RU486), an antisense oligodeoxynucleotide (ODN) for PR mRNA, and an antibody against PR. The results clearly demonstrate that P4 played a physiological role in advancing the diurnal changes of both TIDA neuronal activity and PRL surge through specific PR.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Except for one experiment using serial blood sampling, all rats in the other experiments were decapitated at specific time points during the day, without anesthesia. In experiments in which all rats were killed at the same time point (1300 h), it was done in two days, to avoid any major time delay. The brains were quickly removed and frozen on dry ice. The trunk blood of each rat was collected and centrifuged to obtain the serum sample. Thick (600 µm) coronal brain sections were made with a tabletop freezing microtome and thaw-mounted onto glass slides. The ME region was removed from the sections, using a modified micropunch technique (26), and was stored in 40 µl of 0.15 M sodium phosphate buffer containing 0.65 mM sodium octanesulfonate, 0.5 mM EDTA, 12% ethanol, at pH 2.6. Both ME and serum samples were stored at -20 C until assayed.
In one experiment, the rats were implanted with intraatrial catheters 3 days before the experiment for serial blood sampling using the method previously reported (8). All the rats stayed undisturbed in their home cages (one in each cage) during the blood sampling, and the blood (0.3 ml/sample) was withdrawn from outside of the cage through an extension tubing connected to the implanted catheter. The blood was immediately mixed with an equal amount of PBS containing heparin and was centrifuged to obtain the diluted plasma sample, which was stored at -20 C until assayed. An equal amount of warm (37 C) heparinized saline was replaced into the rat through the catheter each time after the blood sampling. In the experiments that used intracerebroventricular (icv) injections, a 23-gauge stainless steel tubing (10 mm long) was implanted into the lateral ventricle of each rat 6 days before the experiment.
Experimental design
In the first experiment, serial blood samples at 0800, 1000,
1200, 1300, 1400, 1500, 1700, and 1900 h were taken from each
OVX+E2 and OVX+E2+P4 (2 mg/kg) rat.
Only plasma PRL levels were determined in this study.
In the second experiment, both OVX+E2 and OVX+E2+P4 (2 mg/kg) rats were divided into five groups and were decapitated at 1000, 1200, 1300, 1400, or 1500 h. Both ME DOPAC and serum PRL levels were determined in the study.
In the third experiment, various doses of P4 (0.5, 1, 2, or 4 mg/kg) were given to OVX+E2 rats at 0800 h on the experiment day (one group received vehicle as control), and the rats were decapitated at 1300 h. Both ME DOPAC and serum PRL levels were determined in the study.
In the fourth experiment, both OVX and OVX+E2 rats were used. Each rat received either P4 (2 mg/kg) or vehicle at 0800 h and was decapitated at 1300 h. Both ME DOPAC and serum PRL levels were determined in the study.
In the fifth experiment, the OVX+E2+P4 (2 mg/kg) rats were further divided into four groups: one received vehicle as control and the other three received three injections of RU486 (5 mg/kg BW, sc) with different schedules. One received RU486 at 0800, 1000, and 1200 h on the experiment day (1-day schedule). One received RU486 at 0800 and 1200 h on the day before and at 0800 h on the experiment day (2-day schedule). One received RU486 at 0800 h for 3 consecutive days, including the experiment day (3-day schedule). All rats were decapitated at 1300 h on the experiment day. Both ME DOPAC and serum PRL levels were determined in the study.
In the sixth experiment, both OVX+E2 and OVX+E2+P4 (2 mg/kg) rats were used. The OVX+E2+P4 rats were further divided into four groups: one received icv injection of vehicle (3 µl/rat), two received icv injections of either a sense or an antisense strand of synthetic ODN for PR mRNA, and one received RU486 (using the 2-day schedule). The sequences of the sense and antisense ODN for PR mRNA are 5'-TG TTG TCC CCG CTC ATG AGC-3' and 5'-GC TCA TGA GCG GGG ACA ACA-3', respectively, which were adopted from a previous study (27) and synthesized locally (Quality Systems, Inc., Taipei, Taiwan). Each rat received two injections of the ODNs (4 nM each) at 24 and 48 h before death. The rats in the RU486 group also received icv cannulation and vehicle injection. Both ME DOPAC and serum PRL levels were determined.
In the seventh experiment, both OVX+E2 and OVX+E2+P4 (2 mg/kg) rats were used. The OVX+E2+P4 rats were further divided into five groups: one received normal rabbit serum (1:1 dilution, 3 µl/rat, icv) as control, three received icv injections of a monoclonal antibody against PR (Sigma) with one of the dilutions (1:10, 1:5, or 1:1), and one received RU486 (using the 2-day schedule). The diluted antibody or vehicle was injected twice at 24 and 48 h before the animals were killed. The rats in the RU486 group also received icv cannulation and vehicle injection. Both ME DOPAC and serum PRL levels were determined.
In the eighth experiment, intact female rats that showed at least two regular estrous cycles (determined by daily vaginal smears in the morning) were used. Enough rats in the stages of proestrus, estrus, or diestrus I were picked in 1 day, and each group of rats was divided into two: rats in one group were decapitated at 1300 h and, in the other group, at 1500 h. Both ME DOPAC and serum PRL levels were determined.
In the ninth experiment, intact female rats that showed at least two regular estrous cycles were used. RU486 (5 mg/kg BW, sc) was given to rats at 0800 and 1200 h on diestrus II and at 0800 h on proestrus, and the rats were killed at 1300 or 1500 h on proestrus. The control rats received vehicle injection with the same schedule and were decapitated at 1000, 1300, or 1500 h on proestrus. Both ME DOPAC and serum PRL levels were determined.
Assay and statistical analysis
The activity of TIDA neurons was assessed by measuring the
concentration of DOPAC, a major metabolite of dopamine, in the ME, the
terminal region of TIDA neurons. The advantage of the method is that no
pretreatment of enzyme inhibitor is needed, and both ME DOPAC and serum
PRL levels in the same animal can be compared (24).
The levels of DOPAC were determined by HPLC with electrochemical detection, as reported previously (1, 2, 3, 4, 5, 26). In brief, brain samples were thawed, sonicated, and centrifuged. The supernatant was injected into an HPLC-electrochemical detection system (BAS LC480, with PM-80 pump, Rheodyne 7125 injector, phase II ODS column, 3.2 x 10 mm with 3 µm sphere, and LC-4C EC detector, Bioanalytical Systems Inc., West Lafayette, IN). The HPLC mobile phase was identical to the tissue buffer used in storing the punched brain tissues. The flow rate of the pump was 0.8 ml/min, and the oxidizing potential was set at +0.75 V. The tissue pellets were dissolved in 1.0 N NaOH and assayed for protein content (28). Data were expressed as nanograms of DOPAC per milligram of protein. Serum PRL levels were determined by RIA using materials provided by the National Hormone and Pituitary Program of NIDDK, also as described (1, 2, 3, 4, 5, 26). The PRL for iodination was rat PRL I-6, the standard was PRL RP3, and the antibody was antirat PRL S-7. The intra- and interassay coefficients of variance were 5% and 7%, respectively (n = 20).
Statistical analyses were conducted using either two-way (for experiments 1, 2, and 9) or one-way ANOVA (the rest) to test for significant difference among time points and/or treatments. One-way ANOVA, followed by the Student-Newman-Keuls’ multiple-range test, were performed for all groups. Differences were considered significant at P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). A single injection of P4
at 0800 h significantly advanced the surge from 1400 to 1300
h and amplified the surge at all sampling time points
(P < 0.01; Fig. 1). A similar advancement and
amplification of the PRL surge also was found using the decapitation
method (Fig. 2, lower). The
TIDA neuronal activity, using ME DOPAC as the index, had the typical
fall at 1400 and 1500 h in OVX+E2 rats
(P < 0.01; Fig. 2, upper). Treatment of
P4 significantly advanced the decrease, from 1400 to
1300 h, compared with vehicle-treated OVX+E2 rats
(P < 0.01; Fig. 2, upper).
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but not at 0.5 and 1 mg of P4. The effect of P4
(using the effective dose of 2 mg/kg) was only evident in OVX rats
pretreated with E2 (P < 0.01; Fig. 4) but not in OVX rats (Fig. 4).
Treatment of E2 alone slightly elevated the basal PRL level
at 1300 h (P < 0.05; Fig. 4 lower) but
had no significant effect on ME DOPAC level at 1300 h (Fig. 4
upper).
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). Treatments of three
injections of RU486 at 0800, 1000, and 1200 h on the experiment
day had no significant effect on the action of P4 (Fig. 5).
In contrast, the same dosage of RU486 that was spread in 2 or 3 days
before experiment was effective in antagonizing P4’s
effects on ME DOPAC and serum PRL levels at 1300 h
(P < 0.01; Fig. 5). It should be noted that although
serum PRL levels were significantly lowered by RU486, they were still
higher than the control (P < 0.01; Fig. 5
lower).
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). Treatments of two injections of the
sense strand of ODN for PR mRNA had no significant effect on the action
of P4 (Fig. 6). In contrast, same injection of the
antisense ODN significantly antagonized P4’s effects on ME
DOPAC and serum PRL levels at 1300 h (P < 0.01;
Fig. 6), much the same as the 2-day treatment of RU486 (Fig. 6). Though
significantly lowered by antisense ODN treatment, serum PRL levels were
still higher than the control (P < 0.01; Fig. 6
lower).
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). Treatments of various dilutions of a
monoclonal antibody against PR showed a concentration-dependent effect
on preventing the action of P4 (Fig. 7), i.e. no
effect at 1:10, partial effect at 1:5, and significant effect at 1:1
dilution (P < 0.01; Fig. 7). The effect of 1:1
dilution of PR antibody was comparable with that of RU486 (Fig. 7).
Similar to the previous two experiments, serum PRL levels were
significantly lowered by treatments of PR antibody (at 1:5 and 1:1
dilution), but they were still higher than the control
(P < 0.01; Fig. 7 lower).
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). The ME DOPAC levels at 1500 h on
proestrus, estrus, and diestrus I were all significantly lower than
those at 1300 h (P < 0.05; Fig. 8
upper). Significant afternoon PRL surges at 1500 h were
observed in rats on proestrus (P < 0.01) and on estrus
(P < 0.05; Fig. 8 lower) but not on
diestrus I.
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). Treatment of RU486 for 2 days
completely reversed the afternoon decrease of ME DOPAC levels
(P < 0.01; Fig. 9 upper). Serum PRL levels
not only failed to increase at 1300 h (P < 0.05;
Fig. 9 lower), they were also blunted at 1500 h
(P < 0.01; Fig. 9 lower).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We adopted the time schedule for injecting P4 from previous reports of others on PRL and LH secretion (7). It has been shown that P4 needs 4–5 h to exhibit its potentiation effect on PRL secretion. The present finding of P4’s effect on TIDA neuronal activity also supports this notion. In addition, the effective doses of P4 (2 and 4 mg/kg) fell within the ranges used by others (7, 11, 22). Doses less than 2 mg were not effective.
The question of whether P4 has a direct effect on the synthesis or release of PRL in the anterior pituitary is somewhat controversial. Some studies (29, 30) reported no effect; some (31, 32) reported inhibition; and most pointed to a central action in the hypothalamus (19, 20, 21, 22, 23, 33). As stated in the Introduction, the PRs are extensively located in the hypothalamus (13, 14, 15), and their expression depends on the presence of estrogen (14, 15, 16). Our finding also indicates that P4’s effects on TIDA neurons and serum PRL required estrogen pretreatment. Furthermore, we showed that central administration of an antisense ODN and an antibody for PR could prevent the effect of P4. Thus, it is reasonable to state that the main action of P4 may well be in the hypothalamus.
Earlier studies have shown that P4, given for 4–6 h, can lower the TH activity in the hypothalamus and increase the serum PRL level in rats (20, 21). P4 also may be responsible for the low TH mRNA signal observed at 2200 h in proestrous rats (22). Long-term treatment of estrogen plus P4 (for 28 and 14 days, respectively) in spayed rhesus monkeys showed a significant decrease in TH mRNA in the ventral arcuate DA neurons (23). Dopamine level in the hypophysial portal blood has also been shown to be lower on proestrus than on estrus or diestrus (34). On the other hand, P4 has been shown to stimulate dopamine level in the portal blood (19). In general, our results are in agreement with most reports that P4 may have an inhibitory effect on TIDA neuronal activity. However, this is the first report that clearly showed that P4 given at 0800 h invariably lowered ME DOPAC at 1300 h in OVX+E2 rats, which was 1 h before the regular TIDA rhythm begins. This change in TIDA neuronal activity correlates well with an advanced onset of the PRL surge, and it provides an action mechanism for P4’s effect on the PRL surge.
We used three approaches in this study, to answer the question whether the effect of P4 is acting through specific PR, and all the results substantiated our hypothesis. Although all three methods have been successfully used to block the action of P4 (27, 35, 36), and they yielded similar results in this study, their modes of action differ from one another. Both RU486 and the antibody act on competing with P4 to prevent its binding to the PR. RU486 acts as an antagonist to the PR with little agonist activity (36), whereas the antibody binds to the receptor and inactivates it. In addition to being highly potent for binding PR and easy to use, however, RU486 also exhibits high affinity to glucocorticoid receptor (36). Thus, it is desirable to use the receptor antibody to further confirm the result of RU486. The PR antibody we used is from a commercial source, which claims 0.3% cross-reactivity to corticosterone and less than 0.01% to cortisol, estrogen, androgen, and other steroids. For it to work, the antibody must be taken into the neuron intact and in enough concentration to neutralize the PR. That may explain the finding that a higher concentration (1:1 dilution) of antibody was needed.
Using various regimens for administering RU486, we not only showed that P4 was acting through its specific receptors, we also succeeded in finding the optimal time requirement for RU486 to negate the P4’s effect. Pretreatment of RU486 for 20 and 24 h before P4 was effective; whereas simultaneous administration of RU486 with P4 plus two more injections afterwards was not. An earlier study (22), giving a single injection of RU486 at 1200 h on proestrus, failed to prevent the decrease of TIDA neuronal activity at 2200 h either. Whether an action time shorter than 20 h or injection frequencies fewer than 3 times is sufficient to have the effect, remains to be determined.
In contrast, the antisense ODN is designed for binding to the PR mRNA and for blocking the synthesis of PR protein itself (37, 38). Three different antisense ODNs for PR mRNA have been reported (27, 39, 40), and all of them effectively blocked the lordosis behavior induced by P4 in the female rats. The sequence of ODN and the protocol for administering the antisense ODN used in this study were adopted from one of the groups (27, 41), and it has been shown to effectively prevent the expression of PR. The estrogen-induced increase of PR mRNA levels declined by 48 h after the first estrogen injection in OVX rats (42). Because our rats were primed with estrogen implants, we reasoned that it should be necessary to wait at least 48 h before the degradation of existing PR took place and before we could see an effect. We also used the same procedure for injecting the P4 antibody. The antibody, however, may not need as much time for it to work effectively. Nevertheless, the results justified our cause, and we were not looking for the optimal time or dose for blocking the PR at this time.
It should be noted that although the decrease in ME DOPAC concentration
at 1300 h correlated well with the increase in serum PRL level at
that time in all our experiments, those at 1400 and 1500 h did not
(Fig. 2
). There was no further decrease in ME DOPAC level after
1400 h in E2-treated, and after 1300 h in
E2+P4-treated, groups; serum PRL level,
however, continued to rise significantly from 1300 to 1500 h.
Apparently, there are other factors, e.g. the PRL-releasing
factor(s), involved in amplifying the secretion of PRL during the
estrogen-induced afternoon PRL surge, and P4 may further
augment the effect. Again, though treatment of RU486, antisense ODN for
PR mRNA or antibody for PR significantly lowered serum PRL levels
induced by P4 at 1300 h, none of them completely
prevented the increase of serum PRL. These results also indicate that,
in addition to the TIDA neurons, P4 might be acting on
other factor(s) not completely blocked by our treatments. Exactly what
has been stimulated remains to be determined.
We (1, 2, 3, 4, 5, 43) have previously shown that the diurnal change of TIDA neuronal activity is circadian in nature, which can be disrupted by various treatments, e.g. SCN lesion, bombesin, oxytocin, atropine, etc. Because P4 has long been known to have a profound central effect (44, 45), we suspect that the action of P4 on advancing the rhythm may not necessarily be a direct inhibitory effect on the TIDA neurons. Rather, P4 may act on the rhythm-generating machinery to reset the rhythm or to modify the neuronal pathway leading from the SCN to the TIDA neurons. Some preliminary results from this laboratory (46) indicate that P4 may act upon cholinergic, opioidergic, and serotonergic neurons to exert its effect, because pretreatment of their antagonists (i.e. mecamylamine, naloxone, ketanserin) could prevent P4’s effect. These findings may provide important clues for unraveling the underlying mechanisms of P4’s action in the future.
Our previous study (1) showed that the diurnal change of TIDA neuronal activity occurs on all stages of the estrous cycle, be it proestrus, estrus, or diestrus. However, levels at only two time points, i.e. 1000 and 1500 h, were determined in that study. Present findings that the ME DOPAC level at 1300 h of proestrus was significantly lower than those of estrus and diestrus and that pretreatment of RU486 completely prevented the afternoon decrease of TIDA neuronal activity on proestrus strongly suggest a physiological role played by P4 and PR on the preovulatory PRL surge. The recently developed PR knockout mice (47) provide further insight on the importance of PR in reproduction, viz. the mice are unable to ovulate, with attenuated lordosis behavior and lack of mammary gland development. Though PRL surge data were not reported, neither preovulatory LH nor FSH surges are present in those mice (48).
Because the timing of the P4 increase on proestrus (1300–1500 h) is somewhat later than the time we used with exogenous injection (at 0800 h), that makes it difficult to account for the physiological relevance of our treatment. Nevertheless, the present study with proestrous rats did indicate that P4 and its receptors play a physiological role on the diurnal change of TIDA neuronal activity and the PRL surge. Recently, several studies reported a P4-independent way of activating the PR (41, 49, 50). For instance, dopamine and its D1-like agonists have been shown to activate PR in a ligand-independent way through D5 dopamine receptors and to induce the lordosis behavior in female rats (41, 49). Whether dopamine itself may act on PR on proestrus to regulate its own synthesis and release is not known at present, but is an interesting possibility to pursue in the future.
In summary, P4 given to estrogen-primed OVX rats at a specific time of the day could advance the diurnal rhythm of TIDA neuronal activity, which action was dose-, estrogen-, and receptor-dependent. P4 may play an important modulatory role in the timing of the rhythmic changes of TIDA neuron activity and the estrogen-induced afternoon PRL surge on proestrus.
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Acknowledgments |
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Footnotes |
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Received October 9, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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