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Neuroendocrine mechanisms mediating fluid intake during the estrous cycle
Hroirl Kc.\c,dwhHfrlkri~l, Vol. 12.pp. 175-180.1984.0 Ankho
International
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Neuroendocrine Mechanisms Mediating Fluid Intake During the Estrous Cycle
KUCHARCZYK, J. Ric,rrlr,c,/rcloc,~;f~~, ,,ic,c,/ttr,li.\r,r.( rc,grr/trtir~~g flrticl in/trAc clur-i/r,y rhc c~.~twrrs cyc,/c. BRAIN RES BULL 12(2) 175-180. 1984.-Gonadal steroids appear to influence fluid-electrolyte homeostasis through behavioral as well as renal mechanisms. The marked fluctuations in drinking behavior observed during the estrous cycle of the female rat may be due to an interaction between estrogen and the dipsogenic peptide hormone, angiotensin II. at the level of basal forebrain receptors. The preoptic region in particular may play an important integrative role in the maintenance of extracellular fluid balance in synchrony with the estrous cycle, since it contains receptors for angiotensin and estrogen. Prolactin may also directly participate in mechanisms of extracellular thirst, while an exact role for vasopressin has yet to be established. Recent studies also suggest that estrogens may influence body fluid regulation by interacting with several neurotransmitters, including serotonin. dopdmine and norddrenahne. Gonadal steroids Estrogen Angiotensin Prolactin
A
variety
of
physiological
Progesterone Vasopressin
mechanisms
contribute
Fluid-electrolyte
to
of extracellular
‘Requests for reprints Ottawa KIH 8M.5.
fluid
should be addressed
to John Kucharczyk.
Drinking
behavior
The interdependent fluctuations in ingestive behaviors and ovarian steroid secretion during different reproductive states has prompted some speculation that similar or identical control mechanisms are involved 126, 27, 551. However, while ovarian steroids have long been known to influence levels of hormones that regulate the volume and contents of the vascular space [74], the precise nature and locus of any interaction remains obscure. This article will consider several possible neuroendocrine bases which may underlie the association between the estrous cycle and drinking behavior in the cyclic female rat.
the
volume and composition. At the capillary level, the Starling forces promote fluid exchange in accordance with changes in hydrostatic pressure, colloid osmotic pressure, and lymphatic drainage. There are controls intrinsic to the circulation, including the adjustment of cardiac output to venous return, the autoregulation of blood flow in peripheral tissues, and the direct effects of arterial pressure on glomerular filtration and urinary output. As well, there are cardiovascular reflexes involving the autonomic nervous system, adrenal medullary secretions and other vasomotor controls. Finally, a strong endocrine influence is exerted on both renal function and drinking behavior by the renin-angiotensin-aldosterone system, especially in response to internal needs for sodium and water. Recently it has become apparent that gonadal steroids should be added to the list of endocrine factors which can influence fluid-electrolyte balance in mammalian species. In the cyclic female rat, for example, all of the body weight regulating behaviors (water intake, food intake, voluntary exercise) are predictably altered by changes in endogenous levels of the two principal ovarian steroids, estradiol and progesterone 1911. During proestrus and estrus, food and water intakes decrease while activity increases and rats lose weight [SS]. At metestrus and diestrus, when plasma estradiol and progesterone are relatively low [SS], the pattern of behaviors is reversed. Food and water intakes increase, voluntary activity drops sharply, and females gain weight [SS]. Thus, the postpubertal female rat seems to oscillate about a state of fluid and energy balance. regulation
balance
OVARIAN
HORMONE
EFFECTS ON WATER METABOLISM
AND SODIUM
Estrogens operate via both renal and extrarenal mechanisms in producing their sodium- and water-retaining effects. In the rat, urine flow, urinary sodium concentration and sodium excretion rate are lower at estrus than at diestrus, whereas urinary potassium concentration is higher 1201. Both aldosterone and corticosterone, as well as progesterone, are also elevated 1381. Progesterone appears to stimulate aldosterone hypersecretion by opposing the action of this mineralocorticoid on the distal tubule, with resulting natriuresis and reduced blood volume. Estrogens, on the other hand, seem to inhibit the natriuretic effect of progesterone and, in fact, appear to promote sodium reabsorption 1731. The sodium retention induced by estrogen is not accompanied by increased potassium excretion, which indicates that estrogen and aldosterone must inhibit urinary sodium chloride loss via separate mechanisms [ 161. Data Department
I75
of Physiology,
Health
Sciences Center, 451 Smyth
Road.
176
h
from several laboratories suggest that the sodium- and fluidretaining action of estrogen is mediated via extraadrenal mechanisms 141,751including the renin-angiotensin system [ 191. RENIN-ANGIOTENSIN
SYSTEM
The renin-angiotensin system participates in the overall regulation of extracellular fluid volume through direct effects on vascular smooth muscle [SZ], on aldosterone secretion to promote sodium reabsorption [S7], and through its central actions on vasopressin [66] and ACTH [81] secretion, sympathetic activity, and water intake and salt appetite [28]. The early observation by Helmer and Griffith [36] that estrogens cause an increase in plasma renin substrate has been widely confirmed by studies in rats 1631 and human subjects [6,16]. Elevation of plasma renin substrate is frequently accompanied by a rise in plasma renin activity [ 181, aldosterone [56] and circulating angiotensin II IlO]. The marked differences in fluid intake observed during the various estrous stages [27] may therefore parallel primary changes in fluid and electrolyte excretion, or variations in peripheral angiotensin biosynthesis. Alternatively, since gonadal steroids can affect neuronal discharge frequency in areas of the brain that are involved in drinking behavior [49], it seems possible their influence on drinking behavior is due to a modulatory action on central thirst receptors. Some recent work supports this latter interpretation. Findlay et cl/. 1271 tested cyclic female rats for drinking in response to single daily microinjections of equidipsogenic doses of angiotensin 11 and carbachol given through stainless-steel cannulae permanently implanted in the preoptic region of the brain. Angiotensin II caused drinking at all stages of the estrous cycle, but the volumes of water ingested during 1 hr tests on days of vaginal estrus or proestrus were significantly less than on days of diestrus and metestrus. The same estrous cycle-related differences in drinking were observed following peripheral injections of isoprenaline, a ,&adrenergic agonist which stimulates the renin-angiotensin system 1571. In contrast, water intake induced in the same animals following preoptic administration of carbachol, or after subcutaneous injections of hypertonic NaCl, did not vary with the stage of estrous. The cyclic fluctuations in angiotensin-induced drinking were abolished in adult female rats by bilateral ovariectomy, and were absent in prepubertal animals tested daily with intracranial angiotensin. These data indicate that physiological mechanisms for extracellular thirst mediated by renin-angiotensin and those controlling the estrous cycle may interact at the level of the preoptic area. This region of the forebrain is one of the most sensitive central sites for the dipsogenic action of angiotensin 129,831, and has been reported to contain angiotensin receptors (781. At the same time, the importance of the preoptic area for triggering the preovulatory surge of luteinizing hormone is firmly established from electrical stimulation [4] and surgical deafferentation ]35J studies. EStrogen, a known modulator of luteinizing hormone 1341 and luteinizing hormone-releasing hormone secretion 1431, is concentrated by preoptic neurons after systemic administration of labelled steroid 170,951. Perikarya which are luteinizing hormone-releasing hormone positive have been found in the preoptic area [S], and preoptic neurons have been shown to have a differential sensitivity to microiontophoresed estradiol hemisuccinate at various stages of the estrous cycle 1511. Thus this region of the forebrain may play an important
l_i(‘t-I.AK(‘/~‘!\
integrative role in the maintenance of extraiellular fluid b;rl ante in synchrony with the ovarian cycle Another recent study ]SS] found that while injections ol ng doses of angiotensin into the subfomical organ and lateral cerebral ventricles also consistently elicited drinking in adult female rats, the volumes ingested were independent of the stage of estrous. This finding is of interest because the subfornical organ has been shown to contain r-elatively high concentrations of luteinizing hormone-releasing hormone 1.511. and may participate in the regulation of gonadotropin secretion in rats [SS]. As well. anatomical studies have demonstrated neural connections between the aubfornical organ and structures adjacent to the anterior third ventricle. including the median preoptic nucleus 1641.Transfer of peptidergic material, possibly luteinizing hormone-releasing hormone. to the medial preoptic nucleus, organum vasculosum and supraoptic nucleus has been found 1651, prompting the hypothesis that angiotensin receptors in the subfornical organ send excitatory neural inputs to the preoptic area to mobilize drinking behavior [59]. While this possibility has yet to be addressed experimentally using the female rat model, the data currently available suggest that this circumventricular structure does not directly subserve the dipsogenic action of angiotensin during the ovarian cycle. Finally, it would appear that the fluctuations in water intake during the estrous cycle are not secondary to changes in overall fluid-electrolyte metabolism. It has been shown. for example, that whereas drinking induced by angiotensin or isoprenaline fluctuates with the stage of estrous, ingestion of 2.7% NaCl does not [S5]. Furthermore, neither water nor 2.7% NaCl intakes elicited by 24 hr water deprivation differ significantly throughout the phases of estrous 1541. These results provide support for the view that thirst of extracellular origin, in which the renin-angiotensin system is involved 1281, operates through physiological mechanisms distinct from those which mediate drinking due to intracellular dehydration. Only the extracellular mechanisms for body fluid regulation appear to be sensitive to the estrous cycle and changes in ovarian hormones. A major difficulty in pursuing these studies further in the rat is that its small blood volume precludes taking frequent blood samples to analyze levels of estrogens. progesterone, angiotensin and other hormones. Preliminary experiments now underway in young adult gilts are attempting to establish quantitatively the relationship between blood estradiol and progesterone levels and the volumes of water ingested in response to extracellular and cellular thirst stimuli. Nulliparous gilts of the Yorkshire breed weighing 60-90 kg were stereotaxically implanted with 21-gauge stainless-steel guide cannulae aimed at the preoptic region, using surgical procedures previously employed in the dog 1291. Animals were individually housed and maintained on a commercial sodium-free diet with access to tap water and I .8% solution ad lib. Blood samples (10 ml) were collected without stress three times each day via a chronically implanted saphenous catheter. Concentrations of plasma 17p estradiol and progesterone were determined by radioimmunoassay using the method of Van de Weil (‘t trl. [SS] with some modifications. Single intracranial microinjections of 10 ng angiotensin II were made on alternate days over a period of 5 weeks. Fluid intakes for the 1 hr period following the injection were measured in each animal. The results to date indicate that the relative insensitivity of females to extracellular thirst stimuli administered during the estrus stage of the cycle may be due to a declining blood
THIRST
AND THE ESTROUS
CYCLE
estrogen/progesterone ratio. However, as in the rat [.54], the relationship appears to be quite complex: the volumes of water ingested after intracranial injection of angiotensin II were not related to 17p estradio levels measured in peripheral blood samples taken 6 hr before the drinking test. Intakes of 1.8% NaCl tended to increase with increasing blood estradiol concentration, but a large variability in consummatory-response scores for the group as a whole obscured trends that were observed in individual animals. Both water and 1.8% NaCl intakes induced by central angiotensin tended to increase with increases in plasma progesterone up to between 20-30 @ml of steroid. At levels of progesterone in excess of 40 ngiml plasma, water and NaCl drinking elicited by angiotensin was attenuated. RIA measurements of estradiol and progesterone in blood samples taken 4 hr before intracranial administration of angiotensin show that the volume of water ingested is inversely related to estradiol levels while it increases with increasing progesterone levels in some animals. Water intakes, but not I .8% NaCl intakes, were significantly correlated with the estradioliprogesterone ratio in some of the animals. These preliminary data indicate that the influence of the primary ovarian steroids on mechanisms of extracellular thirst mediated by the renin-angiotensin system is complex and may involve other endocrine factors. Some candidate hormones are considered in the next sections. PROLACTIN
Prolactin-induced renal retention of water, sodium and potassium was first demonstrated in the conscious intact rat and in perfused cat kidney nearly 20 years ago [61,62]. However, it is now known that some preparations of prolactin are contaminated with vasopressin 1901. Keeler and Wilson [SO] and Carey, Johanson and Seit [ll] found that when vasopressin-free prolactin was used, there was no evidence for antidiuretic activity. El Karib and Green (241 have shown that prolonged administration of prolactin may, in fact, increase glomerular filtration rate. The effects of prolactin in the renal handling of water and salt therefore warrant careful re-examination. Other data have suggested that this classical “hormone of lactation” may play a direct role in the regulation of drinking behavior. In human subjects acute administration of ovine prolactin has been reported to arouse thirst [40]. Ovine prolactin injected into rats is also dipsogenic 1251, and Kaufman and Mackay [47] found that this increased drinking results from an exaggerated sensitivity of hyperprolactinemic rats to extracellular fluid deficits. Kaufman, Mackay and Scott 1481have shown further that spontaneous 24 hr intakes of water and blood volumes of rats with chronically elevated levels of prolactin were greater than those of controls. Since this was not secondary to increased salt or food intake, the authors proposed 1481that prolactin may have primary dipsogenic activity. Although prolactin and its receptors have been identified in the brain [ 17,921, their relationship to neural thirst mechanisms is not known. Katovich and Simpkins 1441observed that chronic hyperprolactinemia in rats attenuates isoprenaline-induced water intake but has no effect on drinking elicited by angiotensin. They interpreted these data to mean that prolactin acts specifically on /3-adrenergic thirst mechanisms. This may account for the decreased drinking response to isoprenaline during estrous and proestrus 1271 since serum prolactin levels are increased during these stages 12,801. Isoprenaline-
177
induced thirst is also attenuated in rats following estrogen treatment [86], which is known to significantly increase serum prolactin levels in this species [ 131. Thus while a physiological role for prolactin in drinking behavior during the estrous cycle has not been conclusively demonstrated, a variety of data suggest it may participate along with other hormones in extracellular thirst mechanisms. VASOPRESSIN
It is well established that hypovolemia [66] and hyperosmolality (941 both stimulate vasopressin release, and that these effects have homeostatic importance by promoting water conservation. There is also evidence, however, that plasma vasopressin levels fluctuate during the estrous cycle of the rat (791 and the menstrual cycle in women [30,31], apparently in the absence of changes in plasma osmolality or systemic hemodynamics. In the rdt, changes in vasopressin concentration parallel the cyclic fluctuations in endogenous estradiol, peaking during early proestrus, falling in late proestrus, remaining low during estrus. and reaching a nadir at diestrus 1791. As well, in both the rat 1791 and human 130,311, administration of estradiol augments vasopressin release, while progesterone has little or no effect. The rapidity of changes in blood vasopressin levels in the proestrus rat points to enhanced pituitary release of the peptide, rather than an estrogen-induced alteration in its metabolic clearance rate 1791. Some support for this interpretation is gained from studies showing uptake of tritiated estradiol by rat magnocellular neurons [691. A number of ohher reports also indicate that gonadal steroids may modulate vasopressin release. For example, there appears to be a resetting of the osmotic threshold for vasopressin secretion as well as thirst during gestation in the rat [ 231 and human [211, when a decrease in plasma osmolality of several mosmolikg is sustained until term 1211. It has been suggested that the lowered thresholds for vasopressin release and drinking have complementary roles, in that they allow the pregnant female to maintain a new steady-state osmolality within a narrow range 1211. Further research is needed, however, to elucidate the precise mechanisms underlying these observations. In particular, the influence of the renin-angiotensin system on vasopressin release and osmotic thirst thresholds remains to be studied. CURRENT
OUTLOOK
Throughout the estrous cycle of the rat, a large number of target tissues are exposed to constantly changing levels of estrogen and progesterone. Both steroids penetrate the blood-brain barrier relatively easily and are concentrated in specific regions of the CNS [69,70]. Estrogen levels in the hypothalamus of the intact proestrus female, for example, have been estimated to be I to 2 nM [7,8], approximately IO-fold higher than in the systemic circulation at the same stage of the cycle [80]. As described in the article by Meisel and Pfaff elsewhere in this issue, the effects of estrogen. and possibly progesterone. on the brain appear to be based on protein-synthetic genomic interactions with specific neural receptors. There is increasing interest in the mechanism of action of ovarian hormones on neurotransmitter and neuropeptide synthetic processes in the CNS and how these may influence nonreproductive behaviors such as drinking. For example, estrogens have been found to exert a biphasic effect on the
178
density of serotonin receptors in the female rat brain, whereby an acute reduction in receptor concentration is followed by a delayed increase in certain basal forebrain structures [8]. This effect can be mimicked by estradiol in vitro [8]. Biegon and McEwen [8] have proposed that these findings may explain why serotonin receptor density fluctuates in the hypothalamus and preoptic area during the estrous cycle, with a 50% lower density at proestrus than at diestrus. Modulation of serotonin receptors by estrogen may be one of the components required for facilitation of sexual behavior in the female rat [7]. However, serotonin has also been implicated in thirst mechanisms in the rat. When administered in doses above 0.4 mg/kg this biogenic amine causes drinking and a long-lasting hypotension [28]. The effect on water intake appears to be mediated via the renin-angiotensin system since bilaterally nephrectomized animals do not drink after serotonin administration, and ganglionic blockade in the intact rat attenuates both serotonin-induced drinking and renin-release [28]. Close anatomical interrelationships between steroid hormone sites of action and the loci of catecholamine production have also been demonstrated in rat brain 1371. Of particular interest is the finding that P-adrenergic receptors can be down-regulated by estrogens administered in doses similar to those observed in proestrus 1721, since drinking after isoprenaline injections has been shown to vary with the stage of estrous 127, 32, 861. Furthermore, there appears to be a
positive correlation between regional noradrenaline conccn tration and renin substrate concentration in the brain I?‘/. There is also a close correspondence between changes in regional angiotensinogen concentration. the state of hydration of the animal, and the levels of circulating estradiol 112,141. Several of these areas of the brain, including the anterior hypothalamus, preoptic area and septum. contain neural pathways which influence body fluid homeostasis 1551, and it has been suggested that gonadal steroids ma! subserve the function of a “signal mechanism” from the peripheral vasculature to the CNS. Equally intriguing is the recent demonstration that estrogens may be responsible for the altered angiotensin binding observed in female rat pituitary during the estrous cycle [ 141. The physiological significance of angiotensin receptors in the adenohypophysis has not been determined. However, the presence of pituitary binding sites for the peptide indicates that in addition to its influence on central catecholamines and angiotensinogen, estrogen may also modulate the effects of peripherally generated angiotensin on hypophyseal secretions [ 14,821. Angiotensin is known to stimulate vasopressin 1811and prolactin [82] release. and the concentration of each of the three peptides in blood varies with estradiol levels over the course of the estrous cycle 1141.Thus it seems likely that gonadal steroids, but especially estrogen, participate in body fluid homeostasis by influencing drinking behavior a\ well as renal water and salt conservation mechanisms.
REFERENCES 1. Albers, H. E. Gonadal hormones organize and modulate the circadian system of the rat. Am J Physid 241: R62-R66, 1981. 2. Amenomori, Y., C. L. Chen and J. Meites. Serum prolactin levels in rats during different reproductive states. Endorrinolog?: 86: 506-510, 1970. 3. Anhut, H., W. Knepel, A. Holland and D. K. Meyer. /3-Endorphin release by angiotensin II: studies on the mechanism of action. Regul Pept 4: 83-90, 1982. 4. Barraclough, C. A. Sex steroid secretion of reproductive neuroendocrine processes. In: Hundbook ofPhysiology, Emlocrinology, Part I, edited by R. 0. Greep and E. B. Astwood. Baltimore: Waverly Press, 1973, pp. 2P56. 5. Barry, J. and M. P. Dubois. Immunofluorescence study of the preopticoin-fundibular LH-RH neurosecretory pathway of the guinea pig during the estrous cycle. N~,rr,c/rndoc,vin~~/~~~~15: 200-208, 1974. 6. Beckerhoff, R.. J. A. Leutscher, R. Wilkinson, C. Gonzales and G. W. Nokes. Plasma renin concentration. activity and substrate in hypertension induced by oral contraceptives. .I Clin Et7docrinol Mrtab 34: 1067-1077, 1972. 7. Biegon, A., H. Bercovitz and D. Samuel. Serotonin receptor concentration during the estrous cycle of the rat. RvrrirrRvs 187: 221-225, 1980. 8. Biegon, A. and B. S. McEwen. Modulation by estradiol of serotonin, receptors in brain. J Nrurosci 2: 199-205, 1982. 9. Bueno, J. and D. N. Pfaff. Single unit recording in hypothalamus and preoptic area of estrogen-treated and untreated ovariectomized female rats. Bruit7 Res 101: 67-78, 1976. IO. Cain, M. D., W. A. Walters and K. J. Catt. Effects of oral contracentive theraov on the renin-anaiotensin svstem. .I C/~/I E&crinol 33: 671-676, 1971. 11. Carev. R. M.. A. J. Johanson and S. M. Seit. The effects of ovine prolactin on water and electrolyte excretion in man are attributable to vasopressin contamination. .I Clir7 End~~c~ri~7d Mt>rc/h44: 85&858. 1977.
12. Chen, F. M., R. Hawkins and M. P. Printz. Evidence for a functional independent brain-angiotensin system: correlation between regional distribution of brain angiotensin receptors, brain angiotensinogen and drinking during the estrous cycle of rats. In: Tllc, Rer7in A/7,giotc,t7sir7 S.~~/c,nri/r the Brtri,7. Expprrin7~,7to/&wit7 Research. Suppl 4. edited by D. Ganten, M. P. Printz, M. I. Phillips and B. A. Scholkens. Berlin: SpringerVerlag, p. 157. 1982. 13. Chen, C. L. and J. Meites. Effect of estrogen and progesterone on serum and pituitary prolactin levels in ovariectomized rats. G,docrirfology 86: 503-505, 1970. 14. Chen, F. M. and M. P. Printz. Chronic estrogen treatment reduces angiotensin 11 receptors in the anterior pituitary. E/~&Jcri/7o/ogy 113: 1503-1510, 1983. 15. Chesley, L. C. and I. H. Tepper.
Effects of progesterone and estrogen on the sensitivity to angiotensin II. .I Clirr E~7cl~wri~rol lI4etcrh 27: 576-581, 1967. 16. Christy, N. P. and J. C. Shaver. Estrogens and the kidney. /Gfnc,y I/7/6: 306-376. 1976. 17. Clemens, J. A. and B. D. Sawyer. Identification of prolactin in cerebrospinal fluid. Exp Brtrbr Res 21: 399-402, 1974.
18. Crane, M. G. and J. J. Harris, Plasma renin activity and aldosterone excretion rate on normal subjects: I. Effect of ethinyi estradiol and medroxyprogesterone acetate. .I C/i/7E:‘,rtloc~ri/7d 29: 550-557, 1969. 19. Cracker, A. D. Variations in mucosal water and sodium transfer associated with the rat oestrus cycle. J PIIy.sio/ 214: 257-264, 1971. 20. Cracker, A. D. and S. M. Hinsull. Renal electrolyte excretion
during the oestrus cycle in the rat. .I G~tb)c.~irrt~l55: X1.11XLIII, 1972. 21. Davison, J. M., E. A. Gilmore, J. Durr, G. L. Robertson and M. D. Lindheimer. Altered osmotic thresholds for vasopressin secretion and thirst in human pregnancy. Atrr .I Ph,vsio/ 246: F105-F109. 1984.
THIRST AND THE ESTROUS
CYCLE
22. de Vries. G. J., R. M. Buijs and D. F. Swaab. Ontogeny of the vasopressinergic neurons of the suprachiasmatic nucleus and their extrahypothalamic projections in the rat brain-presence of a sex difference in the lateral septum. Brtritl Rc.c 218: 67-78. 1981. 23. Durr, J. A.. B. Stamoutsos and M. D. Lindheimer. Osmoregulation during pregnancy in the rat. .I C/i/l I,r~,cvt 68: 337-346, 1981. 24. El Karib. A. 0. and R. Green. Effect of prolonged administration of prolactin on glomerular filtration rate in the rat../ Physics/ 315: ZIP, 1981. 25. Ensor. D. M.. M. R. Edmondson and J. G. Phillips. Prolactin and dehydration in rats. .I I:/lt/oc~rirro/ 53: Iix-Ix, 1972. 26. Findlay, A. L. R., J. T. Fitzsimons and J. Kucharczyk. Angiotensin-induced drinking fluctuates with the oestrous cycle. .I Plr~siol 270: 4lP, 1978. 77. Findlay. A. L. R., J. T. Fitzsimons and J. Kucharczyk. Dependence of spontaneous and angiotensin-induced drinking in the rat upon the oestrous cycle and ovarian hormones. .I E/lt/oc~!?/rrj/ 82: 2 15-225, 1979. 78. Fitzsimons, J. T. 7h(, P/~~.cio/~,p~ (j/‘ 7/rir.\r o,rt/ Sot/ir/r,l App/i/c. New York: Cambridge University Press. 29. Fitzsimons, J. T. and J. Kucharczyk. Drinking and haemodynamic changes induced in the dog by intracranial injection of components of the renin-angiotensin system. J P/1y.\ir,/ 276: 419-434. 1978. 30. Forsling, M. I*., M. Akerlund and P. Stromberg. Variations in plasma concentrations of vasopressin during the menstrual cycle. .I E/rt/~~c.ri!~o/ 89: 263-266, I98 I 3 I. Forsling. M. I.. , P. Stromberg and M. Akerlund. Effect of ovarian ster-oidz on vasopressin secretion. .I E/rck~c.ri,ro/ 95: 147-151. 1982. 32. Fregly. M. J. Effect of chronic treatment with estrogen on the dipsogenic response of rats to angiotensin. f%or~f~trc~r)/Bioc./rc,,lr Rr/fr/\, 12: 131, 1980. 33. Gaebelein, C. J. and L. C. Senay Jr. Vascular volume dynamics during ergometer exercise at different menstrual phases. E//r .I App/ Plrysi~d 50: l-l I, 1982. 34. Gross, D. S. Effect of castration and steroid replacement on immunoreactive gonadotropin-releasing hormone in the hypothalamus and preoptic area. E,~[/oc,,.i,r~~/~,,~l~,106: l442- 1450, 1980. 35. Halasz. B. The endocrine effects of the isolation of the hypothalamus from the rest of the brain. In: p,.r,,~tic,,..\ i/f &‘~,rr~r,c~rrcl~,I rimdr),yy.vol I, edited by L. Martini and W. F. Ganong. New York: Oxford University Press, 1969, pp. 307-342. 36. Helmer. 0. M. and R. S. Griffith. The effect of the administration of estrogens on the renin-substrate (hypertensinogen) content of rat plasma. Eut/~~ritro/t~:y 51: 421, 1952. 37. Heritage. A. S.. W. E. Stump. M. Sar and L. D. Grant. Brain on the activity of the adrenal cortex and on water and sodium transport. .I El/lcl~~c.ri/r,~/48: IXXiX-IXXX, 1970. 39. Hong, J. S.. K. Yoshikawa. P. M. Hudson and L. L. Uphouse. Regulation of pituitary and brain enkephalin systems by estrogen. I.(/;, .Sc.i 31: 2181-2184. 1982. 40. Horrohin. D. F.. I. J. Lloyd, A. Lipton, P. G. Burstyn. N. Durkin and K. L. Miururi. Actions of prolactin on human renal function. /,trj/c.c,t I: 352-354. 1971. 41. Johnson. J. A., J. 0. Davis, J. S. Baumber and E. G. Schneider. Effects of estrogens and progesterone on electrolyte balances in normal dogs. A/II .I Phy.tio/ 219: 1691-1697. 1970. 42. Kaba. H.. H. Saito, K. Otsuka. K. Seto and M. Kawakami. Effects of estrogen on the excitability of neurons projecting from the noradrenergic A, region to the preoptic and anterior hypothalamic area. 61rtrilr Rc., 274: 15&159. 1983. 43. Kalra, S. P. and P. S. Kalrd. Dynamic changes in hypothalamic LH-RH levels associated with the ovarian steroid-induced gonadotropin surge. Ac,fo k’~~t/~~rirr~d 92: l-7, 1979.
179
44. Katovich, M. J. and J. W. Simpkins. Effects of chronic hyperprolactinaemia on experimentally induced thirsts in male rats. .I E~rt/oc~ri,~o/ 341: 75-83, 1983. 4.5. Kaufman, S. F. A comparison of the dipsogenic responses of male and female rats to a variety of stimuli. (‘(111 .I I’lrx.\irjl Phtrr,,~trc,c*l 58: 118C-I 183. 1980. 46. Kaufman, S. Control of fluid intake in pregnant and lactating rats. J P/!~sio/ 318: 9-16, 1981. 47. Kaufman. S. and B. J. Mackay. Plasma prolactin levels and body fluid deficits in the rat: causal interactions and control of water intake. .I Ph?sio/ 336: 73-81. 1983. 4X. Kaufman, S., B. J. Mackay and J. Z. Scott. Daily water and electrolyte balance in chronically hyperprolactinaemic rat\. .I Ph,v\io/ 321: 11-19. 1981. 49. Kawakami. M. and K. Kubo. Neuro-correlate of limhichypothalamus-pituitary-gonadal axis in the rat: change in limbic-hypothalamic unit activity induced by vaginal and electrical stimulation. Ncrr,.r,olcloc,~;~/~~/~~,~~7: 65-68, 1971. SO. Keeler, R. and N. Wilson. Vasopressin contamination a\ a cause of some apparent renal actions of prolactin. C’tr/l .I PI~y.\iol Pliol-,,ltrc.r>/ 54: 877-890, 1976. 51. Kelly. M. J.. R. L. Moss and C. A. Dudley. Differential sensitivity of preoptic-septal neurons to microelectrophoresed estrogen during the estrous cycle. Brni,~ Rc\ 114: 152-157. lY76. 52. Khairallah. P. A. Pharmacology of angiotensin. In: Kitlrrc,? H~,r/tlo,lc,,s. edited by J. W. Fisher. New York: Academic Press. 1971. pp. 130-163. 53. Kizer. J. S.. M. Pdlkovits and M. J. Brownstein. Releasing factors in the circumventricular organs of the rat brain. Iirlcl01 ri,rt,/r,~?. 98: 3 I l-3 17. 1976. 54. Kucharczyk. J. Effects of gonadal steroids on water and \alt intake induced by angiotensin in the female rat. Sot, N~,ioo.sc~i Ahfr 7: 210-215, 1981. 5s. Kucharczyk. J. Localization of central nervous system structures mediating extracellular thirst in the female rat. .I Et~tloc~ri~~ol. in press. 56. Laidlaw. J. C.. J. L. Ruse and A. G. Gornall. The influence of estrogen and progesterone on aldosterone excretion. .I (‘lit/ El~t/oc,rirlr,/ 22: lhl-171, 1962. 57. Lehr. D., J. Mallow and M. Kurkowski. Copious drinking and simultaneous inhibition of urine flow elicited by beta-adrenergic stimulation and contrary effects of alpha-adrenergic stimulation. J P/?trrr?rclc~o/&p 7‘he, 158: 15&163. 1967. 58. Limonta. P.. R. Maggi. D. Guidici, L. Martini and F. Piva. Role of the subfornical organ (SFO) in the control of gonadotropin secretion. Brtri~ Kc.\ 229: 7.5-84. 1981. 59. Lind, R. W. and A. K. Johnson. Subfornical organ-median preoptic connections and drinking and pressor responses to angiotensin II. .I N~,rr,o.sc.i 2: 1043-1051. 1982. 60. Lloyd. T. and D. Weisz. Direct inhibition of tyrosine hydroxylase activity by catechol estrogens. .I Wir~c~/rr,,,r(‘hc,rrr 253: 4841-4843. 1978. 61. Lockett. M. F. A comparison of the direct renal actions of pituitary growth and lactogenic hormones. .I P/~~.ti~~/ 181: lY2-199, IY65. 62. Lockett. M. F. and B. Neil. A comparative study of the renal actions of growth and lactogenic hormones in rats. .I P/rv\i~~/ 180: 147-156. 1965. 63. Menard. J. and K. J. Catt. Effects of estrogen treatment on plasma renin parameters in the rat. h:,rtlr~cri/!~~l~q~ 92: I%1388. 1973. 64. Miselis. R. R. The efferent projections of the subfornical organ of the rat: A circumventricular organ within a neural network subserving water balance. Rrtri,~ Rcs 230: l-23. lY8l. 65. Miselis. R. R.. R. E. Shapiro and P. J. Hand. Subfornical or-gan efferents to neural systems for control of body water. .S(~i~~rr~~~, 205: 1022-1025, 1979. 66. Mouw. D.. J. Bonjour. R. L. Malvin and A. Vander. Central action of angiotensin in stimulating ADH release. A/jr .I Phr.ri~~/ 220: 239-242. 1971.
180
67. Nunez,
A. A. and F. K. Stephan. The effects of hypothalamic knife cuts on drinking rhythms and the estrus cycle of the rat.
Behav Biol20: 224-234, 1977. 68. PaIlas, K. G., G. J. Holzwarth,
M. P. Stern and C. P. Lucas. The effects of conjugated estrogens on the renin-angiotensin system. J Endocrinol Metub 44: 1061-1068, 1977. 69. Pfaff, D. W. Peptides and steroid hormones and the neural mechanisms for female reproductive behavior. In: The Hyperhalamus, edited by S. Reichlin, R. J. Baldessarini and J. B. Martin. New York: Raven Press. pp. 243-253, 1978. 70. Pfaff, D. W. and M. Keiner. Atlas of estradiol-containing cells in the central nervous system of the female rat. J Camp Nvrtrol 151: 121-128, 1973. 71. Phillips, M. I. and D. Fexlix. Specific angiotensin-II receptive neurons in the cat subfornical organ. Bruin Res 109: 531-540. 1976. 72. Printz, M. P., R. L. Hawkins, C. J. Wallis and F. M. Chem. Steroid hormones as feedback regulators of brain angiotensinogen and catecholamines. Chest 835: 3085, 1983. 73. Radev, A. I. Effect of the sequential use of estradiol and progesterone on the excretion of sodium and potassium and their level in kidney tissue. Probl EndoXrinol (MosX) 19: 91-96. 1973. 74. Saruta, T., G. A. Saade and N. .M. . Kaplan. A possible mech-
-.
anism for hvnertenslon induced by oral contraceptives: UIminished feed-back suppression of renin release. Arch INICYII hiled 126: 621-626, 1970. 75. Shaver, J. C., J. H. Laragh and N. P. Christy. Estrogen-induced edema without hvneraldosteronism. Exerptrc Med Inr Conpr Ser 51: 223-224, 1962: 76. Simonnet, G., B. Bioulac, F. Rodriguez and J. D. Vincent. Evidence of a direct action of angiotensin II on neurons in the septum and in the medial preoptic area. Pharmrrc,ol Biochem Behav 13: 359-363, 1980. 77. Simpson, J. B., A. N. Epstein and J. S. Camardo. Localization of receptors for the dipsogenic action of angiotensin II in the sobfornical organ of the rat. .I Camp Physiol Pswhol 92: 581601, 1978. 78. Sirett, N. E., A. S. McLean,
J. J. Bray and J. I. Hubbard. Distribution of angiotensin II receptors in the rat brain. Broirl Res 122: 299-312, 1977. 79. Skowsky, W. R., L. Swan and P. Smith. Effects of sex steroid hormones on arginine vasopressin in intact and castrated male and female rats. Endocrinology 104: 105-I IO, 1979. 80. Smith, M. S., M. E. Freeman and J. D. Neill. The control of progesterone secretion during the estrous cycle and early pseudopregnancy in the rat: Prolactin, gonadotropin and steroid levels associated with rescue of the corpus luteum of pseudopregnancy. Endocrinology 96: 219-225, 1975.
XI.
D. 0. Characterization of angiotcnsin-mrdiated .A( ‘I‘H release. ~c,ltrf,rndoc,ri~~~~/~~,~~, 36: 249-257. 1983. 82. Steele. M. K., S. M. McCann and A. Negro-Vilar. Modulations by dopamine and estradiol of the central effects of angiotensin ll on anterior pituitary hormone release. /)//c/
International
0361-9230184 $3.00 t .OU
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Neuroendocrine Mechanisms Mediating Fluid Intake During the Estrous Cycle
KUCHARCZYK, J. Ric,rrlr,c,/rcloc,~;f~~, ,,ic,c,/ttr,li.\r,r.( rc,grr/trtir~~g flrticl in/trAc clur-i/r,y rhc c~.~twrrs cyc,/c. BRAIN RES BULL 12(2) 175-180. 1984.-Gonadal steroids appear to influence fluid-electrolyte homeostasis through behavioral as well as renal mechanisms. The marked fluctuations in drinking behavior observed during the estrous cycle of the female rat may be due to an interaction between estrogen and the dipsogenic peptide hormone, angiotensin II. at the level of basal forebrain receptors. The preoptic region in particular may play an important integrative role in the maintenance of extracellular fluid balance in synchrony with the estrous cycle, since it contains receptors for angiotensin and estrogen. Prolactin may also directly participate in mechanisms of extracellular thirst, while an exact role for vasopressin has yet to be established. Recent studies also suggest that estrogens may influence body fluid regulation by interacting with several neurotransmitters, including serotonin. dopdmine and norddrenahne. Gonadal steroids Estrogen Angiotensin Prolactin
A
variety
of
physiological
Progesterone Vasopressin
mechanisms
contribute
Fluid-electrolyte
to
of extracellular
‘Requests for reprints Ottawa KIH 8M.5.
fluid
should be addressed
to John Kucharczyk.
Drinking
behavior
The interdependent fluctuations in ingestive behaviors and ovarian steroid secretion during different reproductive states has prompted some speculation that similar or identical control mechanisms are involved 126, 27, 551. However, while ovarian steroids have long been known to influence levels of hormones that regulate the volume and contents of the vascular space [74], the precise nature and locus of any interaction remains obscure. This article will consider several possible neuroendocrine bases which may underlie the association between the estrous cycle and drinking behavior in the cyclic female rat.
the
volume and composition. At the capillary level, the Starling forces promote fluid exchange in accordance with changes in hydrostatic pressure, colloid osmotic pressure, and lymphatic drainage. There are controls intrinsic to the circulation, including the adjustment of cardiac output to venous return, the autoregulation of blood flow in peripheral tissues, and the direct effects of arterial pressure on glomerular filtration and urinary output. As well, there are cardiovascular reflexes involving the autonomic nervous system, adrenal medullary secretions and other vasomotor controls. Finally, a strong endocrine influence is exerted on both renal function and drinking behavior by the renin-angiotensin-aldosterone system, especially in response to internal needs for sodium and water. Recently it has become apparent that gonadal steroids should be added to the list of endocrine factors which can influence fluid-electrolyte balance in mammalian species. In the cyclic female rat, for example, all of the body weight regulating behaviors (water intake, food intake, voluntary exercise) are predictably altered by changes in endogenous levels of the two principal ovarian steroids, estradiol and progesterone 1911. During proestrus and estrus, food and water intakes decrease while activity increases and rats lose weight [SS]. At metestrus and diestrus, when plasma estradiol and progesterone are relatively low [SS], the pattern of behaviors is reversed. Food and water intakes increase, voluntary activity drops sharply, and females gain weight [SS]. Thus, the postpubertal female rat seems to oscillate about a state of fluid and energy balance. regulation
balance
OVARIAN
HORMONE
EFFECTS ON WATER METABOLISM
AND SODIUM
Estrogens operate via both renal and extrarenal mechanisms in producing their sodium- and water-retaining effects. In the rat, urine flow, urinary sodium concentration and sodium excretion rate are lower at estrus than at diestrus, whereas urinary potassium concentration is higher 1201. Both aldosterone and corticosterone, as well as progesterone, are also elevated 1381. Progesterone appears to stimulate aldosterone hypersecretion by opposing the action of this mineralocorticoid on the distal tubule, with resulting natriuresis and reduced blood volume. Estrogens, on the other hand, seem to inhibit the natriuretic effect of progesterone and, in fact, appear to promote sodium reabsorption 1731. The sodium retention induced by estrogen is not accompanied by increased potassium excretion, which indicates that estrogen and aldosterone must inhibit urinary sodium chloride loss via separate mechanisms [ 161. Data Department
I75
of Physiology,
Health
Sciences Center, 451 Smyth
Road.
176
h
from several laboratories suggest that the sodium- and fluidretaining action of estrogen is mediated via extraadrenal mechanisms 141,751including the renin-angiotensin system [ 191. RENIN-ANGIOTENSIN
SYSTEM
The renin-angiotensin system participates in the overall regulation of extracellular fluid volume through direct effects on vascular smooth muscle [SZ], on aldosterone secretion to promote sodium reabsorption [S7], and through its central actions on vasopressin [66] and ACTH [81] secretion, sympathetic activity, and water intake and salt appetite [28]. The early observation by Helmer and Griffith [36] that estrogens cause an increase in plasma renin substrate has been widely confirmed by studies in rats 1631 and human subjects [6,16]. Elevation of plasma renin substrate is frequently accompanied by a rise in plasma renin activity [ 181, aldosterone [56] and circulating angiotensin II IlO]. The marked differences in fluid intake observed during the various estrous stages [27] may therefore parallel primary changes in fluid and electrolyte excretion, or variations in peripheral angiotensin biosynthesis. Alternatively, since gonadal steroids can affect neuronal discharge frequency in areas of the brain that are involved in drinking behavior [49], it seems possible their influence on drinking behavior is due to a modulatory action on central thirst receptors. Some recent work supports this latter interpretation. Findlay et cl/. 1271 tested cyclic female rats for drinking in response to single daily microinjections of equidipsogenic doses of angiotensin 11 and carbachol given through stainless-steel cannulae permanently implanted in the preoptic region of the brain. Angiotensin II caused drinking at all stages of the estrous cycle, but the volumes of water ingested during 1 hr tests on days of vaginal estrus or proestrus were significantly less than on days of diestrus and metestrus. The same estrous cycle-related differences in drinking were observed following peripheral injections of isoprenaline, a ,&adrenergic agonist which stimulates the renin-angiotensin system 1571. In contrast, water intake induced in the same animals following preoptic administration of carbachol, or after subcutaneous injections of hypertonic NaCl, did not vary with the stage of estrous. The cyclic fluctuations in angiotensin-induced drinking were abolished in adult female rats by bilateral ovariectomy, and were absent in prepubertal animals tested daily with intracranial angiotensin. These data indicate that physiological mechanisms for extracellular thirst mediated by renin-angiotensin and those controlling the estrous cycle may interact at the level of the preoptic area. This region of the forebrain is one of the most sensitive central sites for the dipsogenic action of angiotensin 129,831, and has been reported to contain angiotensin receptors (781. At the same time, the importance of the preoptic area for triggering the preovulatory surge of luteinizing hormone is firmly established from electrical stimulation [4] and surgical deafferentation ]35J studies. EStrogen, a known modulator of luteinizing hormone 1341 and luteinizing hormone-releasing hormone secretion 1431, is concentrated by preoptic neurons after systemic administration of labelled steroid 170,951. Perikarya which are luteinizing hormone-releasing hormone positive have been found in the preoptic area [S], and preoptic neurons have been shown to have a differential sensitivity to microiontophoresed estradiol hemisuccinate at various stages of the estrous cycle 1511. Thus this region of the forebrain may play an important
l_i(‘t-I.AK(‘/~‘!\
integrative role in the maintenance of extraiellular fluid b;rl ante in synchrony with the ovarian cycle Another recent study ]SS] found that while injections ol ng doses of angiotensin into the subfomical organ and lateral cerebral ventricles also consistently elicited drinking in adult female rats, the volumes ingested were independent of the stage of estrous. This finding is of interest because the subfornical organ has been shown to contain r-elatively high concentrations of luteinizing hormone-releasing hormone 1.511. and may participate in the regulation of gonadotropin secretion in rats [SS]. As well. anatomical studies have demonstrated neural connections between the aubfornical organ and structures adjacent to the anterior third ventricle. including the median preoptic nucleus 1641.Transfer of peptidergic material, possibly luteinizing hormone-releasing hormone. to the medial preoptic nucleus, organum vasculosum and supraoptic nucleus has been found 1651, prompting the hypothesis that angiotensin receptors in the subfornical organ send excitatory neural inputs to the preoptic area to mobilize drinking behavior [59]. While this possibility has yet to be addressed experimentally using the female rat model, the data currently available suggest that this circumventricular structure does not directly subserve the dipsogenic action of angiotensin during the ovarian cycle. Finally, it would appear that the fluctuations in water intake during the estrous cycle are not secondary to changes in overall fluid-electrolyte metabolism. It has been shown. for example, that whereas drinking induced by angiotensin or isoprenaline fluctuates with the stage of estrous, ingestion of 2.7% NaCl does not [S5]. Furthermore, neither water nor 2.7% NaCl intakes elicited by 24 hr water deprivation differ significantly throughout the phases of estrous 1541. These results provide support for the view that thirst of extracellular origin, in which the renin-angiotensin system is involved 1281, operates through physiological mechanisms distinct from those which mediate drinking due to intracellular dehydration. Only the extracellular mechanisms for body fluid regulation appear to be sensitive to the estrous cycle and changes in ovarian hormones. A major difficulty in pursuing these studies further in the rat is that its small blood volume precludes taking frequent blood samples to analyze levels of estrogens. progesterone, angiotensin and other hormones. Preliminary experiments now underway in young adult gilts are attempting to establish quantitatively the relationship between blood estradiol and progesterone levels and the volumes of water ingested in response to extracellular and cellular thirst stimuli. Nulliparous gilts of the Yorkshire breed weighing 60-90 kg were stereotaxically implanted with 21-gauge stainless-steel guide cannulae aimed at the preoptic region, using surgical procedures previously employed in the dog 1291. Animals were individually housed and maintained on a commercial sodium-free diet with access to tap water and I .8% solution ad lib. Blood samples (10 ml) were collected without stress three times each day via a chronically implanted saphenous catheter. Concentrations of plasma 17p estradiol and progesterone were determined by radioimmunoassay using the method of Van de Weil (‘t trl. [SS] with some modifications. Single intracranial microinjections of 10 ng angiotensin II were made on alternate days over a period of 5 weeks. Fluid intakes for the 1 hr period following the injection were measured in each animal. The results to date indicate that the relative insensitivity of females to extracellular thirst stimuli administered during the estrus stage of the cycle may be due to a declining blood
THIRST
AND THE ESTROUS
CYCLE
estrogen/progesterone ratio. However, as in the rat [.54], the relationship appears to be quite complex: the volumes of water ingested after intracranial injection of angiotensin II were not related to 17p estradio levels measured in peripheral blood samples taken 6 hr before the drinking test. Intakes of 1.8% NaCl tended to increase with increasing blood estradiol concentration, but a large variability in consummatory-response scores for the group as a whole obscured trends that were observed in individual animals. Both water and 1.8% NaCl intakes induced by central angiotensin tended to increase with increases in plasma progesterone up to between 20-30 @ml of steroid. At levels of progesterone in excess of 40 ngiml plasma, water and NaCl drinking elicited by angiotensin was attenuated. RIA measurements of estradiol and progesterone in blood samples taken 4 hr before intracranial administration of angiotensin show that the volume of water ingested is inversely related to estradiol levels while it increases with increasing progesterone levels in some animals. Water intakes, but not I .8% NaCl intakes, were significantly correlated with the estradioliprogesterone ratio in some of the animals. These preliminary data indicate that the influence of the primary ovarian steroids on mechanisms of extracellular thirst mediated by the renin-angiotensin system is complex and may involve other endocrine factors. Some candidate hormones are considered in the next sections. PROLACTIN
Prolactin-induced renal retention of water, sodium and potassium was first demonstrated in the conscious intact rat and in perfused cat kidney nearly 20 years ago [61,62]. However, it is now known that some preparations of prolactin are contaminated with vasopressin 1901. Keeler and Wilson [SO] and Carey, Johanson and Seit [ll] found that when vasopressin-free prolactin was used, there was no evidence for antidiuretic activity. El Karib and Green (241 have shown that prolonged administration of prolactin may, in fact, increase glomerular filtration rate. The effects of prolactin in the renal handling of water and salt therefore warrant careful re-examination. Other data have suggested that this classical “hormone of lactation” may play a direct role in the regulation of drinking behavior. In human subjects acute administration of ovine prolactin has been reported to arouse thirst [40]. Ovine prolactin injected into rats is also dipsogenic 1251, and Kaufman and Mackay [47] found that this increased drinking results from an exaggerated sensitivity of hyperprolactinemic rats to extracellular fluid deficits. Kaufman, Mackay and Scott 1481have shown further that spontaneous 24 hr intakes of water and blood volumes of rats with chronically elevated levels of prolactin were greater than those of controls. Since this was not secondary to increased salt or food intake, the authors proposed 1481that prolactin may have primary dipsogenic activity. Although prolactin and its receptors have been identified in the brain [ 17,921, their relationship to neural thirst mechanisms is not known. Katovich and Simpkins 1441observed that chronic hyperprolactinemia in rats attenuates isoprenaline-induced water intake but has no effect on drinking elicited by angiotensin. They interpreted these data to mean that prolactin acts specifically on /3-adrenergic thirst mechanisms. This may account for the decreased drinking response to isoprenaline during estrous and proestrus 1271 since serum prolactin levels are increased during these stages 12,801. Isoprenaline-
177
induced thirst is also attenuated in rats following estrogen treatment [86], which is known to significantly increase serum prolactin levels in this species [ 131. Thus while a physiological role for prolactin in drinking behavior during the estrous cycle has not been conclusively demonstrated, a variety of data suggest it may participate along with other hormones in extracellular thirst mechanisms. VASOPRESSIN
It is well established that hypovolemia [66] and hyperosmolality (941 both stimulate vasopressin release, and that these effects have homeostatic importance by promoting water conservation. There is also evidence, however, that plasma vasopressin levels fluctuate during the estrous cycle of the rat (791 and the menstrual cycle in women [30,31], apparently in the absence of changes in plasma osmolality or systemic hemodynamics. In the rdt, changes in vasopressin concentration parallel the cyclic fluctuations in endogenous estradiol, peaking during early proestrus, falling in late proestrus, remaining low during estrus. and reaching a nadir at diestrus 1791. As well, in both the rat 1791 and human 130,311, administration of estradiol augments vasopressin release, while progesterone has little or no effect. The rapidity of changes in blood vasopressin levels in the proestrus rat points to enhanced pituitary release of the peptide, rather than an estrogen-induced alteration in its metabolic clearance rate 1791. Some support for this interpretation is gained from studies showing uptake of tritiated estradiol by rat magnocellular neurons [691. A number of ohher reports also indicate that gonadal steroids may modulate vasopressin release. For example, there appears to be a resetting of the osmotic threshold for vasopressin secretion as well as thirst during gestation in the rat [ 231 and human [211, when a decrease in plasma osmolality of several mosmolikg is sustained until term 1211. It has been suggested that the lowered thresholds for vasopressin release and drinking have complementary roles, in that they allow the pregnant female to maintain a new steady-state osmolality within a narrow range 1211. Further research is needed, however, to elucidate the precise mechanisms underlying these observations. In particular, the influence of the renin-angiotensin system on vasopressin release and osmotic thirst thresholds remains to be studied. CURRENT
OUTLOOK
Throughout the estrous cycle of the rat, a large number of target tissues are exposed to constantly changing levels of estrogen and progesterone. Both steroids penetrate the blood-brain barrier relatively easily and are concentrated in specific regions of the CNS [69,70]. Estrogen levels in the hypothalamus of the intact proestrus female, for example, have been estimated to be I to 2 nM [7,8], approximately IO-fold higher than in the systemic circulation at the same stage of the cycle [80]. As described in the article by Meisel and Pfaff elsewhere in this issue, the effects of estrogen. and possibly progesterone. on the brain appear to be based on protein-synthetic genomic interactions with specific neural receptors. There is increasing interest in the mechanism of action of ovarian hormones on neurotransmitter and neuropeptide synthetic processes in the CNS and how these may influence nonreproductive behaviors such as drinking. For example, estrogens have been found to exert a biphasic effect on the
178
density of serotonin receptors in the female rat brain, whereby an acute reduction in receptor concentration is followed by a delayed increase in certain basal forebrain structures [8]. This effect can be mimicked by estradiol in vitro [8]. Biegon and McEwen [8] have proposed that these findings may explain why serotonin receptor density fluctuates in the hypothalamus and preoptic area during the estrous cycle, with a 50% lower density at proestrus than at diestrus. Modulation of serotonin receptors by estrogen may be one of the components required for facilitation of sexual behavior in the female rat [7]. However, serotonin has also been implicated in thirst mechanisms in the rat. When administered in doses above 0.4 mg/kg this biogenic amine causes drinking and a long-lasting hypotension [28]. The effect on water intake appears to be mediated via the renin-angiotensin system since bilaterally nephrectomized animals do not drink after serotonin administration, and ganglionic blockade in the intact rat attenuates both serotonin-induced drinking and renin-release [28]. Close anatomical interrelationships between steroid hormone sites of action and the loci of catecholamine production have also been demonstrated in rat brain 1371. Of particular interest is the finding that P-adrenergic receptors can be down-regulated by estrogens administered in doses similar to those observed in proestrus 1721, since drinking after isoprenaline injections has been shown to vary with the stage of estrous 127, 32, 861. Furthermore, there appears to be a
positive correlation between regional noradrenaline conccn tration and renin substrate concentration in the brain I?‘/. There is also a close correspondence between changes in regional angiotensinogen concentration. the state of hydration of the animal, and the levels of circulating estradiol 112,141. Several of these areas of the brain, including the anterior hypothalamus, preoptic area and septum. contain neural pathways which influence body fluid homeostasis 1551, and it has been suggested that gonadal steroids ma! subserve the function of a “signal mechanism” from the peripheral vasculature to the CNS. Equally intriguing is the recent demonstration that estrogens may be responsible for the altered angiotensin binding observed in female rat pituitary during the estrous cycle [ 141. The physiological significance of angiotensin receptors in the adenohypophysis has not been determined. However, the presence of pituitary binding sites for the peptide indicates that in addition to its influence on central catecholamines and angiotensinogen, estrogen may also modulate the effects of peripherally generated angiotensin on hypophyseal secretions [ 14,821. Angiotensin is known to stimulate vasopressin 1811and prolactin [82] release. and the concentration of each of the three peptides in blood varies with estradiol levels over the course of the estrous cycle 1141.Thus it seems likely that gonadal steroids, but especially estrogen, participate in body fluid homeostasis by influencing drinking behavior a\ well as renal water and salt conservation mechanisms.
REFERENCES 1. Albers, H. E. Gonadal hormones organize and modulate the circadian system of the rat. Am J Physid 241: R62-R66, 1981. 2. Amenomori, Y., C. L. Chen and J. Meites. Serum prolactin levels in rats during different reproductive states. Endorrinolog?: 86: 506-510, 1970. 3. Anhut, H., W. Knepel, A. Holland and D. K. Meyer. /3-Endorphin release by angiotensin II: studies on the mechanism of action. Regul Pept 4: 83-90, 1982. 4. Barraclough, C. A. Sex steroid secretion of reproductive neuroendocrine processes. In: Hundbook ofPhysiology, Emlocrinology, Part I, edited by R. 0. Greep and E. B. Astwood. Baltimore: Waverly Press, 1973, pp. 2P56. 5. Barry, J. and M. P. Dubois. Immunofluorescence study of the preopticoin-fundibular LH-RH neurosecretory pathway of the guinea pig during the estrous cycle. N~,rr,c/rndoc,vin~~/~~~~15: 200-208, 1974. 6. Beckerhoff, R.. J. A. Leutscher, R. Wilkinson, C. Gonzales and G. W. Nokes. Plasma renin concentration. activity and substrate in hypertension induced by oral contraceptives. .I Clin Et7docrinol Mrtab 34: 1067-1077, 1972. 7. Biegon, A., H. Bercovitz and D. Samuel. Serotonin receptor concentration during the estrous cycle of the rat. RvrrirrRvs 187: 221-225, 1980. 8. Biegon, A. and B. S. McEwen. Modulation by estradiol of serotonin, receptors in brain. J Nrurosci 2: 199-205, 1982. 9. Bueno, J. and D. N. Pfaff. Single unit recording in hypothalamus and preoptic area of estrogen-treated and untreated ovariectomized female rats. Bruit7 Res 101: 67-78, 1976. IO. Cain, M. D., W. A. Walters and K. J. Catt. Effects of oral contracentive theraov on the renin-anaiotensin svstem. .I C/~/I E&crinol 33: 671-676, 1971. 11. Carev. R. M.. A. J. Johanson and S. M. Seit. The effects of ovine prolactin on water and electrolyte excretion in man are attributable to vasopressin contamination. .I Clir7 End~~c~ri~7d Mt>rc/h44: 85&858. 1977.
12. Chen, F. M., R. Hawkins and M. P. Printz. Evidence for a functional independent brain-angiotensin system: correlation between regional distribution of brain angiotensin receptors, brain angiotensinogen and drinking during the estrous cycle of rats. In: Tllc, Rer7in A/7,giotc,t7sir7 S.~~/c,nri/r the Brtri,7. Expprrin7~,7to/&wit7 Research. Suppl 4. edited by D. Ganten, M. P. Printz, M. I. Phillips and B. A. Scholkens. Berlin: SpringerVerlag, p. 157. 1982. 13. Chen, C. L. and J. Meites. Effect of estrogen and progesterone on serum and pituitary prolactin levels in ovariectomized rats. G,docrirfology 86: 503-505, 1970. 14. Chen, F. M. and M. P. Printz. Chronic estrogen treatment reduces angiotensin 11 receptors in the anterior pituitary. E/~&Jcri/7o/ogy 113: 1503-1510, 1983. 15. Chesley, L. C. and I. H. Tepper.
Effects of progesterone and estrogen on the sensitivity to angiotensin II. .I Clirr E~7cl~wri~rol lI4etcrh 27: 576-581, 1967. 16. Christy, N. P. and J. C. Shaver. Estrogens and the kidney. /Gfnc,y I/7/6: 306-376. 1976. 17. Clemens, J. A. and B. D. Sawyer. Identification of prolactin in cerebrospinal fluid. Exp Brtrbr Res 21: 399-402, 1974.
18. Crane, M. G. and J. J. Harris, Plasma renin activity and aldosterone excretion rate on normal subjects: I. Effect of ethinyi estradiol and medroxyprogesterone acetate. .I C/i/7E:‘,rtloc~ri/7d 29: 550-557, 1969. 19. Cracker, A. D. Variations in mucosal water and sodium transfer associated with the rat oestrus cycle. J PIIy.sio/ 214: 257-264, 1971. 20. Cracker, A. D. and S. M. Hinsull. Renal electrolyte excretion
during the oestrus cycle in the rat. .I G~tb)c.~irrt~l55: X1.11XLIII, 1972. 21. Davison, J. M., E. A. Gilmore, J. Durr, G. L. Robertson and M. D. Lindheimer. Altered osmotic thresholds for vasopressin secretion and thirst in human pregnancy. Atrr .I Ph,vsio/ 246: F105-F109. 1984.
THIRST AND THE ESTROUS
CYCLE
22. de Vries. G. J., R. M. Buijs and D. F. Swaab. Ontogeny of the vasopressinergic neurons of the suprachiasmatic nucleus and their extrahypothalamic projections in the rat brain-presence of a sex difference in the lateral septum. Brtritl Rc.c 218: 67-78. 1981. 23. Durr, J. A.. B. Stamoutsos and M. D. Lindheimer. Osmoregulation during pregnancy in the rat. .I C/i/l I,r~,cvt 68: 337-346, 1981. 24. El Karib. A. 0. and R. Green. Effect of prolonged administration of prolactin on glomerular filtration rate in the rat../ Physics/ 315: ZIP, 1981. 25. Ensor. D. M.. M. R. Edmondson and J. G. Phillips. Prolactin and dehydration in rats. .I I:/lt/oc~rirro/ 53: Iix-Ix, 1972. 26. Findlay, A. L. R., J. T. Fitzsimons and J. Kucharczyk. Angiotensin-induced drinking fluctuates with the oestrous cycle. .I Plr~siol 270: 4lP, 1978. 77. Findlay. A. L. R., J. T. Fitzsimons and J. Kucharczyk. Dependence of spontaneous and angiotensin-induced drinking in the rat upon the oestrous cycle and ovarian hormones. .I E/lt/oc~!?/rrj/ 82: 2 15-225, 1979. 78. Fitzsimons, J. T. 7h(, P/~~.cio/~,p~ (j/‘ 7/rir.\r o,rt/ Sot/ir/r,l App/i/c. New York: Cambridge University Press. 29. Fitzsimons, J. T. and J. Kucharczyk. Drinking and haemodynamic changes induced in the dog by intracranial injection of components of the renin-angiotensin system. J P/1y.\ir,/ 276: 419-434. 1978. 30. Forsling, M. I*., M. Akerlund and P. Stromberg. Variations in plasma concentrations of vasopressin during the menstrual cycle. .I E/rt/~~c.ri!~o/ 89: 263-266, I98 I 3 I. Forsling. M. I.. , P. Stromberg and M. Akerlund. Effect of ovarian ster-oidz on vasopressin secretion. .I E/rck~c.ri,ro/ 95: 147-151. 1982. 32. Fregly. M. J. Effect of chronic treatment with estrogen on the dipsogenic response of rats to angiotensin. f%or~f~trc~r)/Bioc./rc,,lr Rr/fr/\, 12: 131, 1980. 33. Gaebelein, C. J. and L. C. Senay Jr. Vascular volume dynamics during ergometer exercise at different menstrual phases. E//r .I App/ Plrysi~d 50: l-l I, 1982. 34. Gross, D. S. Effect of castration and steroid replacement on immunoreactive gonadotropin-releasing hormone in the hypothalamus and preoptic area. E,~[/oc,,.i,r~~/~,,~l~,106: l442- 1450, 1980. 35. Halasz. B. The endocrine effects of the isolation of the hypothalamus from the rest of the brain. In: p,.r,,~tic,,..\ i/f &‘~,rr~r,c~rrcl~,I rimdr),yy.vol I, edited by L. Martini and W. F. Ganong. New York: Oxford University Press, 1969, pp. 307-342. 36. Helmer. 0. M. and R. S. Griffith. The effect of the administration of estrogens on the renin-substrate (hypertensinogen) content of rat plasma. Eut/~~ritro/t~:y 51: 421, 1952. 37. Heritage. A. S.. W. E. Stump. M. Sar and L. D. Grant. Brain
179
44. Katovich, M. J. and J. W. Simpkins. Effects of chronic hyperprolactinaemia on experimentally induced thirsts in male rats. .I E~rt/oc~ri,~o/ 341: 75-83, 1983. 4.5. Kaufman, S. F. A comparison of the dipsogenic responses of male and female rats to a variety of stimuli. (‘(111 .I I’lrx.\irjl Phtrr,,~trc,c*l 58: 118C-I 183. 1980. 46. Kaufman, S. Control of fluid intake in pregnant and lactating rats. J P/!~sio/ 318: 9-16, 1981. 47. Kaufman. S. and B. J. Mackay. Plasma prolactin levels and body fluid deficits in the rat: causal interactions and control of water intake. .I Ph?sio/ 336: 73-81. 1983. 4X. Kaufman, S., B. J. Mackay and J. Z. Scott. Daily water and electrolyte balance in chronically hyperprolactinaemic rat\. .I Ph,v\io/ 321: 11-19. 1981. 49. Kawakami. M. and K. Kubo. Neuro-correlate of limhichypothalamus-pituitary-gonadal axis in the rat: change in limbic-hypothalamic unit activity induced by vaginal and electrical stimulation. Ncrr,.r,olcloc,~;~/~~/~~,~~7: 65-68, 1971. SO. Keeler, R. and N. Wilson. Vasopressin contamination a\ a cause of some apparent renal actions of prolactin. C’tr/l .I PI~y.\iol Pliol-,,ltrc.r>/ 54: 877-890, 1976. 51. Kelly. M. J.. R. L. Moss and C. A. Dudley. Differential sensitivity of preoptic-septal neurons to microelectrophoresed estrogen during the estrous cycle. Brni,~ Rc\ 114: 152-157. lY76. 52. Khairallah. P. A. Pharmacology of angiotensin. In: Kitlrrc,? H~,r/tlo,lc,,s. edited by J. W. Fisher. New York: Academic Press. 1971. pp. 130-163. 53. Kizer. J. S.. M. Pdlkovits and M. J. Brownstein. Releasing factors in the circumventricular organs of the rat brain. Iirlcl01 ri,rt,/r,~?. 98: 3 I l-3 17. 1976. 54. Kucharczyk. J. Effects of gonadal steroids on water and \alt intake induced by angiotensin in the female rat. Sot, N~,ioo.sc~i Ahfr 7: 210-215, 1981. 5s. Kucharczyk. J. Localization of central nervous system structures mediating extracellular thirst in the female rat. .I Et~tloc~ri~~ol. in press. 56. Laidlaw. J. C.. J. L. Ruse and A. G. Gornall. The influence of estrogen and progesterone on aldosterone excretion. .I (‘lit/ El~t/oc,rirlr,/ 22: lhl-171, 1962. 57. Lehr. D., J. Mallow and M. Kurkowski. Copious drinking and simultaneous inhibition of urine flow elicited by beta-adrenergic stimulation and contrary effects of alpha-adrenergic stimulation. J P/?trrr?rclc~o/&p 7‘he, 158: 15&163. 1967. 58. Limonta. P.. R. Maggi. D. Guidici, L. Martini and F. Piva. Role of the subfornical organ (SFO) in the control of gonadotropin secretion. Brtri~ Kc.\ 229: 7.5-84. 1981. 59. Lind, R. W. and A. K. Johnson. Subfornical organ-median preoptic connections and drinking and pressor responses to angiotensin II. .I N~,rr,o.sc.i 2: 1043-1051. 1982. 60. Lloyd. T. and D. Weisz. Direct inhibition of tyrosine hydroxylase activity by catechol estrogens. .I Wir~c~/rr,,,r(‘hc,rrr 253: 4841-4843. 1978. 61. Lockett. M. F. A comparison of the direct renal actions of pituitary growth and lactogenic hormones. .I P/~~.ti~~/ 181: lY2-199, IY65. 62. Lockett. M. F. and B. Neil. A comparative study of the renal actions of growth and lactogenic hormones in rats. .I P/rv\i~~/ 180: 147-156. 1965. 63. Menard. J. and K. J. Catt. Effects of estrogen treatment on plasma renin parameters in the rat. h:,rtlr~cri/!~~l~q~ 92: I%1388. 1973. 64. Miselis. R. R. The efferent projections of the subfornical organ of the rat: A circumventricular organ within a neural network subserving water balance. Rrtri,~ Rcs 230: l-23. lY8l. 65. Miselis. R. R.. R. E. Shapiro and P. J. Hand. Subfornical or-gan efferents to neural systems for control of body water. .S(~i~~rr~~~, 205: 1022-1025, 1979. 66. Mouw. D.. J. Bonjour. R. L. Malvin and A. Vander. Central action of angiotensin in stimulating ADH release. A/jr .I Phr.ri~~/ 220: 239-242. 1971.
180
67. Nunez,
A. A. and F. K. Stephan. The effects of hypothalamic knife cuts on drinking rhythms and the estrus cycle of the rat.
Behav Biol20: 224-234, 1977. 68. PaIlas, K. G., G. J. Holzwarth,
M. P. Stern and C. P. Lucas. The effects of conjugated estrogens on the renin-angiotensin system. J Endocrinol Metub 44: 1061-1068, 1977. 69. Pfaff, D. W. Peptides and steroid hormones and the neural mechanisms for female reproductive behavior. In: The Hyperhalamus, edited by S. Reichlin, R. J. Baldessarini and J. B. Martin. New York: Raven Press. pp. 243-253, 1978. 70. Pfaff, D. W. and M. Keiner. Atlas of estradiol-containing cells in the central nervous system of the female rat. J Camp Nvrtrol 151: 121-128, 1973. 71. Phillips, M. I. and D. Fexlix. Specific angiotensin-II receptive neurons in the cat subfornical organ. Bruin Res 109: 531-540. 1976. 72. Printz, M. P., R. L. Hawkins, C. J. Wallis and F. M. Chem. Steroid hormones as feedback regulators of brain angiotensinogen and catecholamines. Chest 835: 3085, 1983. 73. Radev, A. I. Effect of the sequential use of estradiol and progesterone on the excretion of sodium and potassium and their level in kidney tissue. Probl EndoXrinol (MosX) 19: 91-96. 1973. 74. Saruta, T., G. A. Saade and N. .M. . Kaplan. A possible mech-
-.
anism for hvnertenslon induced by oral contraceptives: UIminished feed-back suppression of renin release. Arch INICYII hiled 126: 621-626, 1970. 75. Shaver, J. C., J. H. Laragh and N. P. Christy. Estrogen-induced edema without hvneraldosteronism. Exerptrc Med Inr Conpr Ser 51: 223-224, 1962: 76. Simonnet, G., B. Bioulac, F. Rodriguez and J. D. Vincent. Evidence of a direct action of angiotensin II on neurons in the septum and in the medial preoptic area. Pharmrrc,ol Biochem Behav 13: 359-363, 1980. 77. Simpson, J. B., A. N. Epstein and J. S. Camardo. Localization of receptors for the dipsogenic action of angiotensin II in the sobfornical organ of the rat. .I Camp Physiol Pswhol 92: 581601, 1978. 78. Sirett, N. E., A. S. McLean,
J. J. Bray and J. I. Hubbard. Distribution of angiotensin II receptors in the rat brain. Broirl Res 122: 299-312, 1977. 79. Skowsky, W. R., L. Swan and P. Smith. Effects of sex steroid hormones on arginine vasopressin in intact and castrated male and female rats. Endocrinology 104: 105-I IO, 1979. 80. Smith, M. S., M. E. Freeman and J. D. Neill. The control of progesterone secretion during the estrous cycle and early pseudopregnancy in the rat: Prolactin, gonadotropin and steroid levels associated with rescue of the corpus luteum of pseudopregnancy. Endocrinology 96: 219-225, 1975.
XI.
D. 0. Characterization of angiotcnsin-mrdiated .A( ‘I‘H release. ~c,ltrf,rndoc,ri~~~~/~~,~~, 36: 249-257. 1983. 82. Steele. M. K., S. M. McCann and A. Negro-Vilar. Modulations by dopamine and estradiol of the central effects of angiotensin ll on anterior pituitary hormone release. /)//c/