Vasopressin and oxytocin: hypothalamic modulators of the stress response: a review

Psychoneuroendocrinology, Vol.

11, No. 2, pp. 131 - 140, 1986.

0 3 0 6 - 4 5 3 0 / 8 6 $3.00 + 0.00 Pergamon Journals Ltd.

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VASOPRESSIN A N D OXYTOCIN: HYPOTHALAMIC M O D U L A T O R S OF T H E STRESS RESPONSE: A REVIEW DANIEL M. GIBBS Department of Reproductive Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, U.S.A. (Received 27 March 1985; in final form 29 June 1985)

SUMMARY ACTH secretion is primarily controlled by hypothalamic secretion of c°rtic°tr°pin releasing factor (CRF) into pituitary portal blood. Howeverarginine vasopressin (AVP) and oxytocin(OT) can modulate the actions of CRF and at times may be important mediators of stress-induced ACTH secretion. The relative contributions of CRF, AVP, and OT to the control of ACTH secretion vary with different types of stress. In general, AVP stimulates ACTH secretion in all species studied. OT also stimulates ACTH release in rats but is inhibitory in primates. The involvement of AVP and OT in the control of ACTH secretion may have important implications for physiological and pathological conditions associated with activation of the hypothalamo- hypophysial- adrenal cortical axis, ACTIVATION of the hypothalamo-hypophysial-adrenal cortical axis is particularly important during stress and has been the subject of intense research. Corticotropin releasing factor (CRF), a 41 amino acid peptide isolated by Vale et al. (1981), appears to be essential for the normal hypothalamic control of pituitary A C T H secretion. CRF has been found in pituitary portal blood at concentrations which are sufficient to stimulate A C T H secretion in vitro (Gibbs & Vale, 1982), and the secretion of CRF into the portal blood is increased during certain types of stress (Plotsky, 1985; Gibbs, 1985c). Removal of endogenous CRF by administration of anti-CRF antiserum almost completely blocks the A C T H response to ether stress, suggesting that CRF plays a central role in the A C T H response to stress (Rivier et al., 1982). However, additional hypothalamic hormones, in particular arginine vasopressin (AVP) and oxytocin (OT), appear to modulate the effect of CRF on A C T H secretion and at times appear to play a key part in mediating the A C T H response to stress. This paper will review the evidence which collectively suggests that A V P and OT may be important modulators of the hypothalamic response to stress. RAT STUDIES A VP e f f e c t s on A C T H secretion AVP has enjoyed off-and-on popularity as a putative CRF over the last 30 years (Gillies & Lowry, 1982). AVP is secreted into the hypophysial portal circulation (Zimmerman et al., 1973; Oliver et al., 1977; Recht et al., 1981; Gibbs & Vale, 1983) by neurons which project from the paraventricular nucleus to the external zone of the median eminence (Zimmerman & Silverman, 1983). It also is possible that additional AVP may reach the portal blood by retrograde flow from the posterior pituitary (Oliver et al., 1977; Bergland & Page, 1978), although this route is controversial (Recht et al., 1981). Relatively high concentrations of AVP also may reach the anterior pituitary directly through a capillary plexus shared by the posterior and anterior pituitary (Bergland & Page, 1978). Thus, two distinct populations of neurons supply AVP to the anterior pituitary: parvicellular neurons from the paraventricular nucleus.which terminate in the median eminence, and 131

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magnocellular neurons from the paraventricular and supraoptic nuclei which terminate in the posterior pituitary. Although AVP by itself is a relatively weak secretogogue for A C T H , it markedly potentiates the activity of CRF in vivo (Yates et al., 1971) and in vitro at concentrations similar to those measured in portal blood (Gillies et al., 1982). Specific AVP receptors which are pharmacologically different from the pressor (V,) and antidiuretic (V2) AVP receptors have been identified in the anterior pituitary (Antoni, 1984; Spinedi & NegroVilar, 1984). The mechanism by which AVP stimulates the corticotrope is unknown but does not involve interactions with the CRF receptor (Holmes et al., 1984) or activation of adenylate cyclase (Aguilera et al., 1983). T A B L E 1. E F F E C T S OF DIFFERENT TYPES OF STRESS ON PLASMA

Stress

AVP

OT

AVP AND

OT IN

NON-PRIMATES

Reference

Novel environment 0 0 (Gibbs, in press) Tail-hang 0 + (Gibbs, in press) Restraint 0 + (Lang et al., 1983; Gibbs, 1984a) Swimming 0 + (Lang et aL, 1983) Hypothermia (Gibbs, 1985b) Ether + + (Gibbs, 1984a) Hemorrhage + + (Plotsky et al., 1985a) Electric shock + + (Rosella-Dampman & Summy-Long, 1984) Hypoglycemia + 0 (Plotsky et al., 1985b) Hypoxia + 0 (Stegner et al., 1984) 0 = no effect; + = s t i m u l a t i o n ; = inhibition. AVP secretion into the peripheral circulation is increased during some but not all types of stress (Table I). In general, AVP secretion increases only during severe, physical stresses and not during neurogenic or behavioral stresses, although this distinction may be less clear in female rats (Williams et al., 1985). The dichotomy between physical and neurogenic stress is further supported by the observations that the AVP antagonist, dPTyr(Me)AVP, partially blocks the A C T H response to ether stress (Rivier & Vale, 1983) bttl has no effect on the A C T H response to the stress of a novel environment (Mormede, 1983). There have been relatively few reports of AVP measurements in portal blood during models of stress (see Gibbs, 1985c and Plotsky, 1985 for reviews). Because of the necessity for anesthesia in portal blood measurements, only models for physical stress have been tested. In each model--serotonergic activation of A C T H (Gibbs & Vale, 1983), hemorrhage (Plotsky et al., 1985a), hypoglycemia (Plotsky et al., 1985b), and hypothermia (Gibbs, 1985b)--portal blood levels of AVP changed in parallel with those of A C T H in the general circulation. The accumulating evidence suggests that AVP may play a physiologic role in the regulation of A C T H secretion, but this probably occurs only in response to severe physical stress. O T e f f e c t s on A C T H secretion

OT is a neurohypophysial hormone which is involved in the milk let-down reflex of suckling and the control of uterine contractility at the time of parturition. Evidence suggests that OT may function as a hypothalamic releasing factor. High concentrations of OT have been detected in hypophysial portal blood (Gibbs, 1984b; Horn et al., 1985), and OT-containing nerve terminals have been identified in the external zone of the median

AVP ANDOT DURINGSTRESS

133

eminence near the primary portal capillaries (Vandesande and Dierickx, 1975; Burlet et al., 1979; Kawata et al., 1983). Like AVP, high concentrations of O T probably reach the anterior pituitary f r o m both the median eminence via the portal blood and the posterior pituitary via direct capillary connections a n d / o r retrograde flow to the median eminence. O T binding has been demonstrated to anterior pituitary cells obtained from estrogenprimed female rats (Rettori, Petrovic & McCann, personal communication). OT can stimulate prolactin (PRL) secretion both in vivo and in vitro (Lumpkin et al., 1983), and O T levels in portal blood increase in parallel with peripheral levels of P R L during the rat estrous cycle (Sarkar & Gibbs, 1984). In addition, O T can block T R H induced T S H secretion, an effect which may allow T R H to function as a PRL-releasing factor during suckling without stimulating T S H release (Frawley et al., 1985). Although these findings suggest that O T may have a role in the control of P R L release, relatively high concentrations of OT are required to influence P R L and TSH secretion, and the physiological significance of these effects is still uncertain. Evidence suggesting that O T may be important in the regulation of A C T H secretion is more convincing. Lutz-Bucher et al. (1982) showed that O T injected into rats bearing an antero-lateral cut around the hypothalamus stimulated corticosterone secretion. Antoni et al. (1983) first demonstrated that, like AVP, O T can potentiate the ability of CRF to stimulate A C T H secretion in vitro. We (Gibbs et al., 1984) and others (Vale et al., 1983) have confirmed the potentiating effect of O T at concentrations similar to those found in the portal blood. As shown in Fig. 1, OT by itself is even less potent than AVP in its ability to release A C T H from superfused rat hemipituitaries. However, it is equal to AVP in its ability to potentiate the activity of CRF. There is no apparent interaction between O T and A V P in releasing A C T H , and other data suggest that O T does not act through the 800

I H

A

600 Z

W: 400

E 200

,T OT

AVP

CRF

AVP

CRF

CRF

OT

OT

AVP

+

+

+

FIG. 1. Effects of OT (10-*M), AVP (10-*M), and CRF (10-gM)alone and in combination on ACTH secretion by superfused rat hemipituitaries. The bars represent the areas under the response curves in arbitrary units. CRF and AVP alone produced a significant increase in ACTH secretion; OT alone had no effect. However, the same concentration of OT markedly potentiated the ACTH response to CRF but had no effect on the ACTH response to AVP. Reproduced from Gibbs et al. (1984).

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AVP receptor (Antoni, 1984). In vivo, the stimulatory effect of OT on A C T H secretion also has been shown to require the presence of endogenous CRF (Rivier & Vale, 1985). In rats, OT is secreted into the peripheral circulation in response to some types of stress (Table I). Although relatively few stress models have been studied, OT secretion generally seems to be enhanced during neurogenic or behavioral stresses, unlike AVP secretion which is not affected by these types of stress (Lang et al., 1983; Gibbs, 1984a). OT secretion also appears to be altered by physical stimuli such as ether inhalation (Gibbs, 1984a), hypothermia (Gibbs, 1985b), electric shock (Rosella-Dampman & Summy-Long, 1984), and hemorrhage (Plotsky et al., 1985a), suggesting that OT secretion may be a more general response to stress than that of AVP. However, an interesting exception to this generalization is the stress of a novel environment, in which neither OT nor AVP levels in peripheral plasma are increased, despite a three-fold increase in plasma A C T H (Gibbs, in press). Studies in which OT, AVP, and CRF were measured in the same samples of hypophysial portal blood have revealed some interesting relationships among these hormones during stress. Although there are several examples of changes in A C T H secretion which are clearly associated with changes in hypothalamic secretion of CRF (Gibbs & Vale, 1983; Plotsky & Vale, 1984), two situations have been described in which changes in A C T H secretion appear to be mediated by increases or decreases in the secretion of OT a n d / o r AVP, while that of CRF remains unchanged. For example, we found that during hypothermia, a condition associated with decreased secretion of A C T H , portal blood concentrations of CRF were not altered, while those of OT and AVP were decreased. Further in vitro and in vivo studies suggested that the decreased release of OT and AVP caused a reduction in pituitary responsiveness to a fixed amount of CRF, so, although the presence of CRF in the portal blood was necessary, the actual change in A C T H secretion was mediated by changes in the release of OT and AVP (Gibbs, 1985b). Plotsky et al. (1985b) described a very similar situation associated with hypoglycemiainduced A C T H secretion. Here, too, CRF concentrations in portal blood were unchanged by the stress of hypoglycemia, whereas AVP concentrations increased. To establish a functional link between stress-induced increases in OT and A C T H , we studied the effect of injections of anti-OT antiserum on stress-induced A C T H secretion. As shown in Fig. 2, 0.5 ml of a highly specific anti-OT antiserum injected 1 h before tailhanging stress resulted in a 59°70 inhibition of the stress-induced A C T H response, suggesting that endogenous OT is necessary for a normal A C T H response to this stress (Gibbs, 1985d). O f interest, anti-OT antiserum had no effect on A C T H secretion in stress paradigms not associated with increased O T secretion (Gibbs, in press). This suggests that basal levels of OT have no appreciable direct or permissive effects on A C T H secretion and that it is not until O T levels rise in response to stress that the potentiating effects of OT are expressed. Additional evidence suggesting a physiologic role for neurohypophysial peptides in the control of A C T H secretion in rats has been reported by Fagin et al. (1985). Removal of the posterior lobe of the pituitary in rats had no effect on the A C T H response to physical stress (hemorrhage or surgery) but markedly attentuated the response to neurogenic stress (noise or novel environment). Posterior lobectomy also interfered with the normal circadian variation in A C T H and corticosterone secretion.

A V P AND OT DURINGSTRESS

150

---]Stressed ~ A m

-r I0

I0C

135

I

NonStressed

T T

50

0

0

0

0.05

0.5

A N T I - O T ANTISERUM (ml) FIG. 2. Effect of anti-OT antiserum on stress-induced A C T H secretion. Rats were injected with anti-OT antiserum or normal rabbit serum as a control 1 h before being suspended by the tail for 3 min. The larger dose of antiserum caused a 59% reduction in stress-induced A C T H release ( p < 0.005). Reproduced from Gibbs (1985d). P R I M A T E STUDIES

In primates, A V P appears to influence the secretion of A C T H in much the same way as it does in rats. For example, in humans A V P has been shown to potentiate the activity of C R F both in vivo ( L i u e t al., 1983; DeBold et al., 1984) and in vitro (Lamberts et al., 1984). However, the role of O T during stress seems to be quite different in primates compared to rats. Legros et al. (1982a) found that OT infusions in humans had an inhibitory effect on hypoglycemia-induced A C T H secretion, in contrast to their potentiating effect in rats. Legros et al. (1984) also reported that the inhibitory effect of OT infusions on A C T H and cortisol secretion occurred with infusion rates producing plasma O T concentrations as low as 10 lxlU/ml (about 22 ng/ml), which are within an order of magnitude of those found in rat hypophysial portal blood (Gibbs, 1984b). Inhibition of the pituitary - adrenal axis by small amounts of OT also has been reported by Coiro et al. (1985). However, Lewis & Sherman (1985) could not demonstrate an inhibitory effect of OT on A C T H secretion in humans under very similar conditions. No in vitro studies have yet been done in primates to determine if the apparent inhibitory effect of O T occurs at the level of the pituitary or at some other site in the CNS. We have investigated the effect of a neurogenic stress on peripheral plasma concentrations of O T in Rhesus monkeys. The animals were placed in a small confinement cage and exposed to a loud bell for 30 min. Plasma OT levels fell significantly by more than 30°/o within 15 min of the onset of stress, while plasma A C T H levels rose about two-fold. Plasma A V P levels also rose slightly, but the increase did not achieve statistical significance. In a separate experiment, non-stressed monkeys were treated with dexamethasone (1 m g / k g / d a y ) for 4 days. By day 4, A C T H levels were about 60°7o lower than on day 0, and OT levels were more than three times higher (Kalin et al., 1985). In a preliminary study of six human cancer patients undergoing whole-body hyperthermia as part of a treatment protocol, we found that plasma OT levels were lower

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during the hyperthermic period, at a time when A C T H levels were markedly increased. In three patients there was a rebound increase in O T secretion above baseline following termination of the stress (Kalin & Gibbs, unpublished data). Legros et al. (1982b) also reported an inverse relationship between A C T H and O T - n e u r o p h y s i n in one h u m a n subject during the psychic stress of anticipating an insulin tolerance test. In primates, OT and A C T H are released in an inverse fashion, and OT tends to inhibit A C T H release. In rats, OT and A C T H are usually released in parallel, and OT enhances A C T H release. The reasons for these marked differences between species are not clear. There is evidence in rats that neurohypophysial peptides can inhibit CRF release when injected into the third ventricle (Plotsky et al., 1984). It is possible that in primates a central inhibitory effect of OT predominates, while in the rat the dominant effect is stimulation at the level of the pituitary. Further work is necessary to resolve this intriguing discrepancy.

CONCLUSIONS

The growing body of evidence reviewed in this paper strongly suggests that AVP and OT are at times involved in the modulation of A C T H secretion during stress. In the rat, both peptides enhance A C T H secretion and are themselves secreted in response to some, but not all, types of stress. In general, OT seems to be more important during neurogenic or " e m o t i o n a l " stress, whereas AVP may play a role in the A C T H response to physical stress. Much less information exists about the role of these peptides in primates, but it appears that O T secretion is inversely related to A C T H secretion, and that OT inhibits A C T H secretion. There are several important implications of these findings. The involvement of OT and AVP in the regulation of A C T H secretion during some but not all types of stress illustrates the heterogeneity of the response to different types of stress, as well as the multifactorial and redundant control of the hypothalamic-hypophysial-adrenal axis (Fig. 3). This apparent redundancy not only probably serves to fine-tune the system but also may provide backup control in the event of partial dysfunction (Beny & Baertschi, 1980). It should be mentioned that the functions of AVP and OT during stress may go beyond the regulation of A C T H secretion. For example, AVP is important in the maintenance of plasma volume and blood pressure during shock (Robertson, 1977). AVP and OT have been shown to have opposite effects on the consolidation and retrieval of memory (Kovacs and Telegdy, 1982). Although the effects of stress on brain levels of these peptides are not known, it is interesting to speculate that possible amnesic actions of OT might have adaptive value in minimizing the emotional trauma of certain stresses. Finally, OT receptors ( K d = 5 X 10-gM) have been demonstrated on fat cells (Bonne & Cohen, 1975), and OT in concentrations greater than 2 × 10-'°M will stimulate gluconeogenesis in rat hepatocytes (Whitton el a l . , 1978). The physiological significance of these metabolic effects is still unclear. The ability to measure peripheral plasma concentrations of these two hypothalamic peptides involved in the regulation of the stress response should provide new approaches not only to the study of stress, but also to the understanding of other psychological and physical conditions which cause dysfunction of the hypothalamo-hypophysial-adrenal cortical axis.

AVP AND OT

DURINGSTRESS

137

Stress

!

Hypothalamus

I~-,

Ir~--I re~ r ~ 7 ~ / X \ / / ,

i nteri°r I

....

Pituitary

J

Adrenal~

.

.

.

.

.

FIG. 3. Schematic representation of the hypothalamo-hypophysial-adrenalaxis. Stimulatory effects are shown as solid lines and inhibitory effects as dashed lines. Stress alters the secretion of one or more of the hypothalamic factors which interact at the pituitary to increase the secretion of ACTH. The presence of CRF is necessary but not always sufficient, as stress-induced increases in ACTH secretion may at times be mediated by changes in the secretion of AVP, OT, and epinephrine (EPI). EPI can be released by both the adrenal medulla and the hypothalamus (Gibbs, 1985a). Adrenal glucocorticoids inhibit pituitary secretion of ACTH directly, as well as indirectly by inhibiting hypothalamic secretion of CRF (Plotsky & Vale, 1984) and AVP but probably not OT (Robinson et al., 1983; Koenig et al., 1985). *(In primates, the effect of OT on ACTH secretion is inhibitory, not stimulatory.) Research from the author's laboratory was supported by a Mellon Foundation Faculty Scholar Award and by NIH grant AM-32517.

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