Life Sciences, Vol. 46, pp. 1407-1420 Printed in the U.S.A.

Pergamon Press

MINIREVIEW THE PHYSIOLOGY AND MECHANISMS OF THE STRESSINDUCED CHANGES IN PROLACTIN SECRETION IN THE RAT Richard R. Gala Department of Physiology Wayne State University School of Medicine Detroit, MI 48201USA (Received in final form March 8, 1990) Summary It is well known that stress in a number of forms induces the secretion of prolactin (PRL) in a number of species. What is not well known is that under certain conditions stress will also induce a decrease in PRL secretion. The conditions whereby stress decreases PRL are those where PRL secretion is elevated such as during the proestrous afternoon surge and during the nocturnal surge of pseudopregnancy. The physiologic significance of the stress-induced increase of PRL is suggested to be important in maintaining the competence of the immune system. The significance of the stress-induced decrease of PRL does not appear to have a major consequence on the physiology of reproduction in the rat and it is suggested that future studies be directed towards its significance in the immune system. The literature is reviewed dealing with the regulation of PRL secretion with emphasis on the factors that generate PRL surges in the rat. In addition the mechanism(s) of the stress-induced increase and decrease is (are) also examined. A hypothesis is presented suggesting an interaction between tuberoinfundibular dopamine secretion and a hypothalamic prolactin releasing factor in the generation of PRL surges and the differential effects of stress on PRL secretion. 1:

INTRODUCTION

Early studies by Meites and associates indicated that stress in a number of forms released prolactin (PRL) as evidenced by marmnary gland growth and stimulation of milk secretion (I). Grosvenor and co-workers observed that ether stress decreased pituitary PRL when introduced during lactation (2). However, it was Neil1 who first demonstrated that immunoassayable plasma PRL increased when the animals was exposed to ether stress (3). Since these initial observations a number of investigators have demonstrated that stress, in a number of forms and in a number of species, increases plasma PRL (4-7). Although an increase in plasma PRL to stress is well known to most investigators what is less well known is that stress under certain conditions decreases plasma PRL. The paradoxical effect of stress on PRL release was first demonstrated by Rothchild and associates when they observed that ether, when applied during the afternoon of proestrus, decreased, rather than 0024-3205190 $3.00 +.oo Copyright (c) 1990 Pergamon Press plc

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increased, plasma PRL (8). This observation was rapidly confirmed by others (9910). We observed that restraint stress induced a similar response in suppressing PRL release as did ether and that in addition when restraint was introduced in the early afternoon just prior to the afternoon PRL surge an increase in PRL was observed but when introduced during the afternoon surge a decrease was observed (11). This suggested that it was not the time of day that determined the response to stress but the level of PRL secretion. If indeed the level of PRL secretion determined the response to stress then stress introduced during times when PRL is elevated, as during the nocturnal surge of pseudopregnancy and pregnancy in the rat, should also decrease plasma PRL. We have recently reported that restraint stress introduced either during the nocturnal surge of pseudopregnancy (12) or of pregnancy (13) suppressed PRL secretion. II. A.

Physiologic Significance

Stress-Induced Increase of Prolactin

The physiologic significance of the stress-induced increase in PRL is not known. However, evidence is emerging that PRL is important in maintaining the competence of the immune system (14,15). In primates sleep induces a marked increase in plasma PRL and the physiologic significance of this endogenously induced rhythm is also unknown but again the immune system has been suggested as the physiologic target of this increase in PRL. Stress also elevates glucocorticoids which suppresses PRL secretion (16,17) and the immune system. Although the elevation of glucocorticoids to stress appears to be counterproductive to maintaining a competent immune system new evidence and a fresh interpretation of old data suggests this may not be the case. Munck and associates (18) have proposed the idea that the elevation of glucocorticoids as a result of stress acts as a brake on the immune system so that it does not become hyperactive and disrupt normal homeostasis - i.e., the induction of autoimmune diseases. Thus at times of stress PRL increases may help to activate the immune system while glucocorticoids modulate the system so that it is in physiologic control. In addition, PRL receptors have been identified in other tissues not directly involved in immune responses suggesting that the stress-induced PRL increase may have other physiologic functions. B.

Stress-Induced Decrease of Prolactin

The surges of PRL that occurred during the afternoon of proestrous and during pseudopregnancy and pregnancy have physiologic significance to the reproductive function of the rat. The proestrous afternoon surge has an luteolytic effect on the corpora lutea from the previous cycle. This has been clearly demonstrated by a number of investigators using dopamine (DA) agonists which block the proestrous afternoon PRL surge and prevent the lysis of corpora lutea from the previous cycle (19,20). Since stress also blocks the afternoon surge we examined its influence on ovarian function. Although restraint stress significantly suppressed the proestrous PRL surge we found little effect on corpora lutea number, number of ova ovulated in the subsequent cycle, estrous cycle length and the incidence of pregnancy or pseudopregnancy (21). Although the proestrous PRL surge was markedly decrease, it was never completely blocked by restraint stress (plasma PRL was approximately 100 ng/ml). Apparently this level of PRL during the afternoon of proestrous is adequate to induce a luteolytic action on the corpora lutea. During pseudopregnancy (22) and the first half of pregnancy (23) the rat has two daily PRL surges. One occurs approximately at the time of the

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afternoon proestrous surge while the other occurs in the early morning hours and is called the nocturnal surge. These surges have a luteotrophic action, that is, they rescue the corpora lutea of the estrous cycle from destruction and induce the secretion of progesterone which maintains pseudopregnancy or the early phase of pregnancy (24). The disruption of these surges results in terminating pseudopregnancy or pregnancy. Since we observed that restraint stress suppresses the nocturnal surge, we undertook a study to determine its effect on pseudopregnancy and pregnancy. A daily stress-induced decrease of the nocturnal surge significantly decreased plasma progesterone and shortened We had previously reported that the blockade pseudopregnancy by 2 days (13). of the nocturnal surge with 2-a-bromoergocryptine, a DA agonist, disrupted pseudopregnancy in 50% of the animals and extended the duration of the afternoon surge (25). No such extension of the afternoon surge, however, was evident in animals whose nocturnal surge was suppressed by restraint stress (13). In pregnant animals the stress-induced decrease of the nocturnal surge during the first half of pregnancy resulted in 50% of the animals terminating pregnancy (13). Plasma progesterone, however, was not significantly altered when compared to non-stressed animals and of those animals administered pimozide, to block the stress-induced decrease of the nocturnal surge, 50% of them also terminated their pregnancy (13). Thus the termination of pregnancy by stress could not be attributed to a decrease in PRL and progesterone but to some factor(s) unknown at the present time. In general, the physiologic consequences of the stress-induced decrease of PRL surges in rat are minimal at best. The reason for this is probably due to the inability of stress to completely block PRL surges. Although stress decreases the surges by 70-80% the remaining amount of PRL is apparently adequate to maintain near normal reproductive physiology. Thus, it appears that the wrong physiologic parameter was examined. Future studies should be directed to determining-the.influence of PRL surges on the immune system and the consequences of their suppression.

III. A.

Mechanisms of the Stress-Induced Chanqes

Regulation of the Stress-Induced Increase of Prolactin

The stress-induced increase of PRL is of a low magnitude and of a short duration. We reported that in adrenalectomized animals a greater stressinduced increase in PRL occurred when compared to intact animals and that the increase was sustained for as long as the stressful stimulus was applied (17). We further noted that the i-v. administration of corticosterone completely blocked the stress-induced increase of PRL and as the corticosterone was metabolized from circulation and stress was continued, plasma PRL increased (17). Thus, the short-lived increase in PRL release due to stress is due to the suppressive effect of the concomitant increase in adrenal glucocorticoids. Although early investigations indicated that a decrease in tuberoinfundibular dopamine (TIDA) activity mediated the stress-induced PRL increase (26,27) recent investigations have indicated that this might not be the complete picture. A number of years ago Reichlin and co-workers reported that animals treated with reserpine had a ether-induced PRL release comparable to non-reserpine treated animals and suggested that the ether-induced PRL release was mediated by a prolactin releasing factor (PRF) (28). Subsequent studies by Shin in which animals were infused with DA to suppress PRL secretion, the exposure to ether resulted in PRL release comparable to non-dopamine infused animals (29). Further, other investigators using audiogenic stress did not observe a change in median eminence DA (30) and Gibbs (31), using heat stress in a carefully controlled study, observed an increase in plasma prolactin but no change in portal blood DA. These studies and others suggest that the

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stress-induced increase in PRL is induced by a PRF and that DA may not necessarily be involved in the stress-induced increase in PRL. Why then has Moore and co-workers and others consistently observed changes in TIDA activity to stress? It is believed that the key to this controversy is the method of inducing stress. In most cases where ether was used as the stressor, TIDA neuronal activity was decreased as reported by Moore and co-workers (27, they etherized their animals prior to immobilization stress). In cases where stress was induced without ether, such as in our study (32) no changes in TIDA activity was observed. In a recent study by Lookingland, Gunnet, Toney and Moore (personal communication) they showed that in female rats, tube restraint produced no effect on the activity of TIDA neurons but increased plasma PRL and that pre-exposure to ether enhanced the effect of tube restraint on plasma PRL levels while decreasing the activity of TIDA neurons. Thus stress can induce the release of PRL without the participation of DA, however, the introduction of ether will have an additive effect on PRL and suppress TIDA neuronal activity.

In order for a hypothalamic peptide to be considered as a PRF certain criteria should be met: 1. It should stimulate PRL release directly at the anterior pituitary both with and without the addition of dopamine to the culture medium. Explants of the pituitary rather than cells would approximate most closely the physiologic condition to demonstrate this response. 2. Its concentration in portal blood should be higher than in peripheral blood and a higher concentration should exist during PRL surge periods. 3. High concentrations of the peptide should be present in the external layer of the median eminence. 4. Lesioning of the cell bodies producing the peptide should eliminate or markedly attenuate surges. 5. The administration of antisera or specific peptide antagonists should block or markedly attenuate surges. 6. The anterior pituitary should have receptors for the peptide. 7. Sex steroids, such as estrogen and progesterone, may alter the concentration of the receptor in keeping with endocrine mileau appropriate for the surge, i.e., estrogen increases receptor concentration during the afternoon PRL surge. A putative PRF should stimulate PRL secretion when administered -in 8. a. What is the evidence implicating a PRF in the stress-induced increase of PRL? Lesions of the hypothalamic paraventricular nuclei, the region where the cell bodies of the putative PRL releasing factors originate, abolishes the increase in PRL induced by stress (33,34) and that induced by serotonin (34) suggesting that serotonin may mediate the stress-induced increase in PRL. Electrolytic lesions of the dorsal or medial raphe, which extensively decreased hypothalamic serotonin concentrations, did not alter stress-induced (foot shock) PRL release (35), however, radiofrequency lesions of the median raphe attenuated the PRL response to itmaobilization stress (36). At the present time there is no way to resolve the conflicting data of raphe lesions except to assume that the extent of the lesions may have differed. Murai and BenJonathan, examining intermedia-posterior pituitary (PP) lobectomized rats reported that the ether-induced PRL release was abolished but not that induced by serotonin (37). Others, however, observed that removal of the PP eliminated the serotonin-induced:PRL increase (38). Thus at present it is not clear whether the stress-induced PRL increase is mediated by serotonin or whether the serotonin-induced PRL release is mediated through the PP. Future investigations are required to resolve these issues.

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Studies examining thyrotropin-releasing hormone (TRH) as the stressinduced PRF are not extensive. Ether stress administered to male rats increases PRL release but exogenous TRH administration has no effect (39). Cold stress introduced to male rats increased serum PRL and prior TRH antiserum administration did not alter the response (40). There have been no studies examining TRH involvement in the stress-induced PRL increase in female rats. The evidence to date, however, indicates that TRH may not be the mediator of the stress-induced PRL release at least in the male rat. The importance of vasoactive intestinal peptide (VIP) as the PRF mediating ether-induced PRL release was examined in lactating rats previously separated from their pups for six hours and allowed a prior 30 minute suckling period before ether exposure. Using this experimental model VIP antisera completely blocked the ether-induced PRL rise (41). Other investigators examining intact male rats exposed to ether reported that prior administration of VIP or peptide histidine isoleucine (PHI) antisera either separately or together attenuated the ether-induced PRL release (42). The simultaneous injection of both antisera gave the greatest suppression of the response but did not completely abolish it. The VIP/PHI system although a strong candidate for physiologic PRL in stress does not appear to be the complete answer since significant increases in PRL can occur even when the system is eliminated. This is not surprising since ether will decrease TIDA neuronal activity in addition to releasing a PRF. Early reports indicated that stress increased oxytocin (OT) levels in the general circulation (43) and decreased hypothalamic concentrations (44). The level of OT in portal blood of animals with their posterior pituitary removed has been reported to be at least 15 times greater than that of the peripheral circulation (45). Stress in the form of restraint or ether but not cold significantly increased peripheral OT levels (46) and the increase in OT paralleled the increase in PRL (47). The effect of stress on portal blood OT levels appears not to have been reported but the administration of potent and specific OT antagonists did not alter either the ether-induced or the 5-HTPinduced PRL release (48). An examination of the effect of OT passive immunization on stress-induced PRL release has also not been reported. Thus a number of studies have indicated that stress releases OT but the OT antagonist data suggests that it may not act alone in the stress-induced PRL increase. The removal of the posterior pituitary, on the other hand, abolishes the ether-induced PRL release (37) suggesting that an unidentified factor from the posterior pituitary plays a significant role. B.

Regulation of the Afternoon Prolactin Surge

In order to understand the mechanisms responsible for the stress-induced decrease of PRL one must first understand the factors responsible for the induction of PRL surges. It was Neil1 and associates who first demonstrated that the proestrous afternoon PRL surge was generated by estradiol and that the actions of estradiol were at the level of the hypothalamus (49). Our work indicated that the most sensitive region in the hypothalamus for the estrogen-induced PRL surge was the medial preoptic area (50). It has been appreciated for some time that PRL secretion is tonically suppressed in situ and that the factor responsible for this suppression is dopamine whi?iifiinates from the TIDA neurons in the hypothalamus (51,52). A number of investigators (53-56), including my laboratory (32), have reported that TIDA neuronal activity is decreased during the afternoon surge suggesting that a decrease in DA secretion is responsible, at least in part, for the afternoon surge. However, the neural regulation of PRL secretion can not be completely accounted for by

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alterations in DA secretion and it is believed that a releasing factor is also involved. A number of chemically characterized neural peptides found in the hypothalamic-median eminence area have been considered as PRF candidates. Thyrotropin-releasing hormone (TRH). The first observed peptide with PRF alctivitywas TRH (57). Thyrotropin-releasing hormone cell bodies found in the paraventricular nuclei have their end terminals in the median eminence (58). Studies examining the proestrous PRL surge (59) and the afternoon PRL surge in ovariectomized, estrogen-treated rats (60) indicated an increase in the concentration of TRH in the portal blood. In the ovariectomized rat the administration of TRH had minimal effects on PRL release but if estrogen was administered TRH receptors were induced and TRH becomes effective in inducing PRL release (61,62). Serotonin has been reported to increase TRH release under a number of experimental conditions (63-65) and while pchlorophenylalanine decreased TRH in the portal blood during the afternoon PRL surge by 50%, a PRL surge was still apparent, but attenuated (60). The administration of an antiserum to TRH prior to the proestrous afternoon PRL surge decreased circulating TSH levels and blocked only the initial aspects of the PRL surge (66,67). Thus, while a number of studies provide data consistent with TRH being the physiologic PRF during the afternoon surge, the antisera data indicates that only the initial part of the surge can be blocked by removing TRH from circulation. Ben-Jonathan and co-workers has suggested that the afternoon PRL surge consists of two phases: the initial part of the surge is brought about by a releasing factor while the later part of the surge is maintained by a decrease in TIDA activity (68). If Ben-Jonathan is correct, then TRH may be a strong candidate for the physiologic PRF in the PRL proestrous afternoon surge. 2. Vasoactive intestinal peptide (VIP). The next hypothalamic peptide to be considered as the physiologic PRF for the afternoon surae of PRL is VIP. Kato and co-workers were'the first to show that VIP had PRF activity (69). A closely related neuropeptide, peptide histidine isoleucine amide (PHI) also stimulates PRL release by way of the VIP receptor (70,71) and it should be appreciated that in our discussion of VIP we may also be discussing PHI action. VIP is also locally produced by the anterior pituitary lactotrope cells and the addition of VIP antisera to anterior pituitarv incubations decreased the --in vitro production of PRL (72-75). Estrogen admjnistration has been reported to decrease (down reaulate?) the concentration of anterior oituitarv VIP receptors (76) althoigh it will increase the concentration of VIP ii the AP (77). The neurons producing the VIP found in the median eminence are located in the paraventricular nucleus of the hypothalamus (78). There are also VIP neurons in the suprachiasmatic nucleus that are innervated by serotonin (79) but these neurons project to the paraventricular nucleus (80). Higher levels of VIP have been detected in hypophysial portal blood than in the periphery (81,82), and serotonin stimulation increased portal blood VIP concentration and stimulated ,PRL release (83). The administration of VIP antisera has been reported to block (84) or partially block (85) the PRL releasing effect of serotonin suggesting ,that serotonin's action in releasing PRL may be partially mediated by VIP release. Serotonin stimulation has been reported by us (86) and others to be important in the generation of the afternoon PRL surge. Fink and co-workers have reported, however, no change in concentration of portal blood VIP during the afternoon PRL surge (87) questioning the significance of VIP as a physiologic PRF during this time. Ben-Jonathan and co-workers, on the other hand, have administered VIP antisera prior to the proestrous PRL surge and observed the suppression of the early phase of the ,afternoon surge (88) suggesting that VIP may indeed be involved in the generation of the surge but not necessarily directly at the anterior pituitary. In addition they also

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noted that medial basal hypothalamic VIP concentration on proestrus was twice that observed on diestrus 1. High levels of VIP binding sites have been detected in the dorsal medial nucleus as well as in the arcuate nucleus of the hypothalamus (89) and VIP administration increased hypothalamic DA concentrations (90) suggesting that VIP stimulates TIDA activity. These latter observations, however, are not consistent with the observation that VIP increases PRL secretion and may relate to some other unknown regulatory function or perhaps in initiating the termination of the PRL afternoon surge. 3. Dxytocin (OT). The next hypothalamic peptide to be considered as the physiologic PRF during the afternoon PRL surge is OT. A number of years ago my laboratory reported that OT (Pitocin) when added to AP explants stimulated PRL secretion (91). This work was recently confirmed by McCann's laboratory (92). Oxytocin cell bodies are found in the paraventricular nuclei of the hypothalamus and their terminations have been identified in the external layer of the median eminence (93,94). Sarkar and Gibbs (95) have observed higher OT levels in the portal blood than in the peripheral circulation and that portal blood levels of OT are elevated during the proestrous afternoon surge. The administration of OT antisera delayed and suppressed the afternoon PRL surge of ovariectomized, estrogen-treated rats (96) and the proestrous surge during the estrous cycle (97). The administration of specific OT antagonists completely block the afternoon proestrous surge but did not alter serotonininduced PRL release (98). Specific OT receptors have been identified in the rat AP and the administration of estrogen increases the concentration of these receptors (99). Although both VIP and OT appear to be strong candidates for PRF during the afternoon surge recent evidence indicates that the induction of PRL release by VIP may be mediated by OT. Samson and co-workers (100) reported that when VIP was injected into the third ventricle plasma OT levels were increased and an antiserum to OT blocked PRL release. Further, the PRL response to intraventricular injection of VIP was blocked by a OT antagonist but not by a VIP antagonist. In addition, the administration of an OT antagonist delayed and blunted the afternoon PRL surge in ovariectomized, estrogen treated rats. Almost simultaneously Arey and Freeman (101) using less direct methods indicated that a OT antagonist suppressed the afternoon PRL rise in ovariectomized animals given a standard dose of domperidone while a VIP antagonist did not. The conclusions from both of these studies is that VIP action is through hypothalamic activation of OT release and OT in turn induces the afternoon surge. 4. Posterior pituitary (PP) PRF. Although a number of other peptides, such as angiotensin II (102), neurotensin (103), bradykinin (104), substance P (105) and others, have been demonstrated to stimulate PRL secretion directly on the anterior pituitary none of them has been examined in adequate detail to be considered at this time as strong candidates for a physiologic PRF. BenJonathan and co-workers, however, have presented data that the posterior pituitary (PP) contains a PRF that is not related to any of the peptides identified to date. Their studies indicated that the removal of the PP in the morning resulted in markedly suppressing the initial phase of PRL surge that afternoon (88). In a subsequent extensive investigation they showed that the PP PRF was not TRH, VIP or OT by using anterior pituitary cell cultures and specific antagonists for each of the peptides (106). They have also recently reported that their PP extract can induce PRL release when administered i.v. into the ovariectomized rat (107). They further indicated that the PP PRF had a molecular weight around 4-5000 and was resistant to trypsin but inactivated by chymotrypsin and proline-specific endopeptidases (106). They envisioned

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this factor to be similar to the oxytocin-vasopressin system with the cell bodies in the hypothalamus (PVN) and the terminals in the PP (106). Early studies by Fagin and Neil1 (108), however, reported that the removal of the PP eight days earlier did not alter the afternoon PRL surge of ovariectomized, estrogen-treated animals. Although this appears to contradict the results of Ben-Jonathan and co-workers (88) it is quite possible that by 8 days neural collaterals of the PP releasing factor may have innervated the portal blood vessels of the median eminence allowing a normal PRL surge to occur. Neil1 and co-workers reported that the vasopressin associate glycopeptide, which had a molecular weight between 4-5000 was capable of stimulating PRL secretion in vitro and an antiserum to it blunted suckling-induced PRL release (109). Although this appeared to be a strong candidate for Ben-Jonathan's PP PRF, Ben-Jonathan and co-workers have recently reported in the Brattleboro rat, which has no vasopressin or its associated glycoprotein, that there is no disruption of the suckling-induced PRL release and that the PP from this strain of rat contain equivalent amounts of PRF as do other strains (110). Thus, it appears that the vasopressin associated glycoprotein is not the PP PRF. In addition in further purification studies the Ben-Jonathan group recently reported that the PP PRF has a molecular weight of close to 1000 (111). As can be appreciated from the above evidence none of the neural peptides discussed can clearly be ascribed as the physiologic PRF inducing the afternoon surge although TRH fits most of the criteria and the PP PRF factor shows considerable promise. C.

Regulation of the Nocturnal Prolactin Surge

The induction of the nocturnal PRL surge can be brought about by cervical stimulation in both intact and ovariectomized rats (112,113). In ovariectomized animals the nocturnal surge is amplified to normal levels by the administration of progesterone (113,114). An understanding of neural factors regulating the surge is almost non-existent. We have recently shown that median eminence DA and dihydroxyphenylacetic acid (DOPAC) levels are decreased during the nocturnal PRL surge in a manner similar to that observed during the afternoon surge (32). Further, Arey and Freeman (101) have recently reported that OT and VIP antagonists blocked the amplified domperidone induced PRL release in ovariectomized rats during the time (0300h) when the nocturnal surge would normally occur in pseudopregnant and pregnant animals. Beyond these two studies there is little evidence of the factors regulating the nocturnal PRL surge. D.

Regulation of the Stress-Induced Decrease of Prolactin

There is very little evidence on the mechanism of the stress-induced decrease of PRL. We have observed that adrenalectomy had little effect on preventing the stress-induced decrease in plasma PRL (12,115). Examining the influence of neural antagonists and agonists on the stress-induced decrease in plasma PRL in the ovariectomized, estrogen-treated rat we reported that neither opiate, cholinergic, nor GABAergic antagonists or agonists had any effect on blocking the stress-induced decrease in plasma PRL (116). The administration of phenoxybenzamine but not phentalamine, both a-adrenergic blockers prevented the stress-induced decrease of PRL. Pimozide, a DA antagonist, prevented the stress-induced decrease suggesting that an increase in DA release mediated the response (116). This suggestion was confirmed by us when we observed that the suppressing effect of restraint stress on the afternoon and nocturnal surges was accompaniqd by an increase in TIDA neuronal activity (32). Thus the only evidence available on the regulation of the stress-induced decrease of PRL is an increase in DA release at the level of the median eminence. A great need exists for additional investigations to

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determine whether other factors, e.g., PRFs, are also involved in this response.

EIAM Ql

PY

** P(O.01vs CONTROL a P(O.01 b P(O.08

**

a

111

CONTROL AM-PM

lo-'Id

10-7Y DOPAMINE

Fig. 1 A comparison of prolactin suppression in vitro by var ous levels of dopamine obtained at 1OOOh (AM) I_._._ anterior. pituitaries . _-__.between and at 1700h (PM) from ovariectomized, estrogen-treated rats. Anterior pituitaries obtained in the afternoon are more sensitive to dopamine. The number in the bars is the number of pituitaries per group. a and b are statistical "t" test comparisons between PM and AM groups. The increase in TIDA activity reported above (32) during the stressinduced decrease of prolactin was a modest one (approx. 21%) but statistically significant. We questioned whether the pituitary during the afternoon PRL surge was more sensitive to DA than the pituitary in the morning. Anterior pituitaries obtained from ovariectomized, estrogen-treated rats at lOOOh were compared to pituitaries obtained at 1700h to determine the effectiveness of DA added -in vitro at the levels of 10e6, lo-' and lo-*M to suppress PRL release using a 1 hour explant incubation system. We found that the pituitary obtained in the afternoon is highly sensitive to PRL suppression by DA (Fig. 1) and probably represents the physiologic consequence of the increase in anterior pituitary DA receptors reported previously (117). Thus, the modest increase in TIDA neuronal activity we observed previously to afternoon stress (32) would have profound effects on suppressing the PRL surge.

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PROPOSED MECHANISM OF STRESS - INDUCED PFIOLACTIN CHANGES

Fig. 2 Proposed mechanism of stress-induced prolactin changes. for explanation.

E.

See text

Hypothesis for the Stress-Induced Changes of Prolactin

A working hypothesis to explain why stress when introduced in the morning, when PRL levels are basal, induces an increase in PRL but when introduced during the PRL surges induces a decrease in PRL is presented in Fig. 2.

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In the morning TIDA activity is high and the secretion of PRF is low and PRL levels are basal (upper left panel). In the afternoon under estrogen influence TIDA activity is decreased while PRF action is increased resulting in a surge of PRL (upper right panel). The termination of the surge occurs when the surge levels of PRL stimulate the TIDA neurons to increase their activity which then attenuates the action of the PRF. In addition, surge levels of PRL may also terminate the release of PRF secretion and plasma PRL return to basal levels. Stress in the morning induces the secretion of a PRF which breaks through the DA inhibition of PRL and allows a short lived, low magnitude pulse of PRL release (lower left panel). Stress also stimulates TIDA activity but since it is already at a high level, there is little to no observed effect. Ether which decreases TIDA activity, will, therefore, augment the PRL response to stress. During the afternoon surge stress reactivates DA secretion from the TIDA neurons and since the anterior pituitary at this time is more sensitive to the PRL suppressing action of DA, it decreases plasma PRL levels to those observed during morning stress but not to basal presurge levels (lower right panel). Stress at this time also acts to stimulate PRF release but since it is already occurring at a high level little to no effect is seen above that observed during morning stress. Although there are other factors that may be involved in this response, such as the amount of releasable PRL in the anterior pituitary at the time of stress and PRF anterior pituitary receptor density, the above description represents a working hypothesis for experiments to be performed in the future. It is also suggested that a PRF is released twice daily in the rat both in the afternoon and in the early morning hours (nocturnal surge) but that DA blocks the effect of PRF so that only a small elevation is observed. In the ovariectomized rat we have reported that a small but statistically significant increase in plasma PRL is evident in the afternoon (118). Further when one blocks DA action in the ovariectomized rat using pimozide we have reported that the increase in PRL in the afternoon is greater than the increase in the morning (116). A similar observation has been recently reported using domperidone as the DA antagonist (119). Thus there is evidence to suggest that a daily surge of PRF occurs in the afternoon and DA markedly suppresses its action on releasing PRL. Estrogen acts not only to initiate a neurogenic stimulus from the hypothalamic medial preoptic area (50) but also directly on the anterior pituitary to alter DA suppression of PRL (62,120), to increase PRF receptors and to increase the amount of releasable PRL. In the nocturnal surge progesterone may have comparable actions on the hypothalamus and anterior pituitary to amplify this surge as does estrogen for the afternoon surge. Thus the PRF stimulus finds the anterior pituitary maximally sensitive to its action. References 1. C.S. NICOLL, P.K. TALWALKER and J. MEITES, Am. J. Physiol. -198 1103-1106

(1960).

2. ;i;65;ROSVENOR, S.M. MCCANN and R. NALLAR, Endocrinology 76 883-889 3. J.D. NEILL, Endocrinology 87 1192-1197 (1970). ODELL, Proc. Sot. Exp. Biol. Med. -136 689693 (1971). 5. J.A. SEGGIE and G.M. BROWN, Can. J. Physiol. and Pharmacol. 53 629-637 (1975). 6. K.S. MATT, M.J. SOARES, F. TALAMANTES and A. BARTKE, Proc. Sot. Exp. Biol. Med. 173 463-466 (1984). 7. G.L. NOEL, m. SUH, J.G. STONE and A.G. FRANTZ, J. Clin. Endocrinol. Metabol. 35 840-851 (1972).

4. H.R. RAUD, C.A. KIDDY and KD.

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