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Inhibitory effect of oxytocin on corticotrope function in humans: are vasopressin and oxytocin ying–yang neurohormones?
Psychoneuroendocrinology 26 (2001) 649–655 www.elsevier.com/locate/psyneuen
Viewpoint
Inhibitory effect of oxytocin on corticotrope function in humans: are vasopressin and oxytocin ying–yang neurohormones? Jean-Jacques Legros
*
Endocrine Service, Psychoneuroendocrine Unit, University of Liege — Sart Tilman, 4000 Lie`ge, Belgium Received 30 November 2000; received in revised form 18 March 2001; accepted 19 March 2001
Abstract Oxytocin (OT) and vasopressin (VP) are very similar neurohypophyseal peptides. While VP is known as an ACTH stimulating factor synergistic to CRF since two decades, the inhibiting activity of OT, first demonstrated in the human, is now confirmed in various species including mouse and rat! It is likely that endogenous oxytocinergic system which can be activated by physiological and/or pharmacological manipulation can “buffer” the stress activated vasopressin-ACTHcortisol action. Since VP and OT share also opposite action on cognitive function, those two “sister” neuropeptides might be considered as “ago-antagonist” or “ying–yang” neurohormones! 2001 Elsevier Science Ltd. All rights reserved. Keywords: Oxytocin; Vasopressin; Adrenals; Stress
1. Historical perspective It is well known that the hypothalamus exerts a stimulatory action on the release of ACTH and cortisol that is mediated by corticotropin releasing hormone (CRH) first isolated in 1981 by Vale and co-workers (Vale et al., 1981). However, decades
* Tel.: +32-4-366-8226; fax: 32-4-366-7261. E-mail address: [email protected] (J.-J. Legros). 0306-4530/01/$ - see front matter 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 3 0 6 - 4 5 3 0 ( 0 1 ) 0 0 0 1 8 - X
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J.-J. Legros / Psychoneuroendocrinology 26 (2001) 649–655
before this discovery, vasopressin (VP) was shown to exert a positive effect on ACTH release in central diabetes insipidus (DI) rats (McCann, 1957) and was therefore considered as a putative corticotropin releasing factor (CRF) until the discovery by Vale. Later research demonstrated that VP acts on the adenohypophyseal cells through a specific calcium dependant receptor V1b (or sometimes V3) different from the kidney (V2) and vascular (V1a) receptors. The actions of VP and CRH are synergistic (Gillies et al., 1982). Further it has been shown that VP plays a specific role in the adrenal response to a neurogenic stress in the rat (Crine et al., 1983; Whithall, 1989; Degoeij et al., 1992). Such an action had been suspected in the human (Legros et al., 1982b) and it was suggested to be at least partly responsible for the dexamethasone non-suppression (or “escape”) that is observed in some depressive patients (Legros et al., 1982a; 1983b; Holsboer, 1988) see review in Scott and Dinan (1998). We have recently shown that peripheral plasma VP-neurophysin was elevated together with ACTH and cortisol after a 2 hour mild stress test in 10 out of 25 non depressed patients who scored high on the Spielberger state anxiety scale thus confirming the role played by the central vasopressinergic system in ACTH regulation during “psychological stress” in non-pathological conditions (Legros et al., 2000). Besides its action at the periphery and at the hypothalamo–hypophyseal level, VP was shown by de Wied (1965) to exert a positive effect on some forms of “memory” in the rat. Such a positive action on cognitive function was later confirmed in humans (Legros et al., 1978). In the same year, Bohus et al. (1978) presented in the rat, the first evidence that oxytocin (OT) the “sister” neurohormone of VP can share and have opposite effects to those of VP on cognitive function, suggesting therefore “agonist–antagonist” actions of the two hormones. Such an inhibitory action of OT on evoked potential and memory tests was later confirmed in humans (Geenen et al., 1988). Recently Heinrichs and co-workers convincingly demonstrated that OT exerts a general amnesic influence on explicit memory, irrespective of the words’ content, whereas the nonapeptide selectively impairs implicit conceptual memory retrieval for words with reproduction-related meaning (Heinrichs et al., 1998). Based on Bohus’ hypothesis, we postulated that OT could also act as an antagonist of VP on ACTH secretion. Available data in the rat generally used dosages 50 to 100 times higher for OT than for VP (Gibbs, 1986; Hary et al., 1993). However, recent work showed that a chronic administration of OT at more physiological doses (1 µg/kg, ICV) caused a sustained decrease in plasma levels of corticosterone in the rat, an action opposite to that of VP (Petersson et al., 1999).
2. Action of exogenous OT on corticotrope function in the human We first demonstrated that IV infusion of 2 IU of OT in six normal male volunteers induced a decrease in cortisol plasma level (Chiodera and Legros, 1981). Later, we demonstrated that this action was dose-dependent (Legros et al., 1984) and related to a decrease of ACTH, thus suggesting an action at the hypothalamo–hypophyseal level (Legros et al., 1982c). However, this inhibitory action was not confirmed in a
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study on four normal males (Lewis and Sherman, 1985). Careful inspection of these later data revealed, however, that two among the four volunteers were obese, a condition known to activate endogenous neuropituitary function (Legros and Franchimont, 1972) and to probably desensitise tissue receptors to low dose infusion of neurohypophyseal peptides. We later confirmed the reproducibility of the sensitivity of corticotrope function in repeated testing compared to placebo in four normal male volunteers; in this study, we also evidenced a “rebound” effect on ACTH and cortisol at the end of the perfusion (Legros et al., 1987). This action of exogenous OT was subsequently confirmed during exercise-induced ACTH and cortisol release (Coiro et al., 1988), during insulin hypoglycemia (Petraglia et al., 1986) and following metyrapone activation (Chiodera and Coiro, 1987) (reviewed in Evans, 1997). The specificity of this action was further demonstrated by the absence of action of exogenous OT on glucagon and calcitonin induced ACTH-cortisol rise in humans (Volpi et al., 1989). The mechanism of action of OT on ACTH release could be competition at the level of the V1b receptor, as suggested by the inhibition of the exogenous VP induced ACTH release in the human (Legros et al., 1982c). Further it was demonstrated, in the rat, that the stimulatory action of OT on ACTH release is mediated by V1b receptors (Schlosser et al., 1994). However, although portal OT concentrations are quite high in humans (Gibbs, 1985), binding capacity of OT to V1b receptor appears to be incompatible with a direct antagonist action of OT on VP receptors (Chan et al., 2000). A partial direct inhibitory action of OT on ACTH effect at the adrenal level has also been demonstrated in normal humans (Legros et al., 1988). Such an inhibitory action of OT on ACTH-induced corticosterone synthesis has been described in “in vitro” and “in vivo” investigations in the rat (Stachowiak et al., 1995). Since corticosterone is hypotensive in the rat, this effect of OT could partly explain the hypotensive influence of exogenous OT observed in the same species (Petersson et al., 1996).
3. Endogenous OT and corticotrop function in the human The first demonstration of a decrease in corticosterone production during an oxytocin mediated process (lactation) was provided by Lightman and Young (1989) in the rat. Later, a relationship between endogenous OT release and corticotrope function was documented during various stresses in the same species (Jezova et al., 1995; Romero et al., 1995; Makara et al., 1996). In humans, the few studies that have been published investigated the simultaneous fluctuation of plasma ACTH and OT during nipple stimulation. Chiodera and coworkers showed an inverse relationship between plasma OT and ACTH levels during suckling in seven lactating women and during breast stimulation in six normally menstruating women (Suh et al., 1986; Chiodera et al., 1991). A similar relationship was confirmed in six breast feeding women by Amico et al. (1994), which is in agreement with an inhibitory influence of endogenous OT on ACTH/cortisol secretion in the very physiological conditions of nipple stimulation.
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4. OT as an endogenous anti-stress neuropeptide in humans In anxious mothers breast feeding is accompanied by relaxation and calm. The possibility that OT plays some role in the reduction of anxiety and/or stress during breast feeding is therefore worth considering (Uvnas-Moberg et al., 1990; Altemus, 1995; Heinrichs et al., 2000). With respect to this hypothesis, a recent study demonstrated that in 25 normal cycling women, a relaxing massage induced an increase in OT blood levels whereas imagery of sad emotions decreased OT (Turner et al., 1999). The same authors also reported that peripheral secretion of OT in response to emotional stimuli is associated with individuals’ interpersonal characteristics (Turner et al., 1999). If this inhibitory action of OT on adrenals is clinically relevant, then pharmacological activation of endogenous OT release by hormones (estrogens) (Legros and Grau, 1973; Legros et al., 1975; McCarthy, 1995) or a psychotropic agent like SSRI (Uvnas-Moberg et al., 1999) might be considered at least partially as a way of alleviating stress. It is also known that alcohol ingestion induces a release of OT-neurophysin in humans (Legros et al., 1983a) and that exogenous OT inhibits the development of tolerance to the incapacitating action of ethanol in rats (Jodogne et al., 1991; Tirelli et al., 1992). OT could then participate not only in the anxiolytic effect of ethanol but could also protect individuals against addiction to this anxiolytic effect (review in Kovacs et al., 1998), a possibility that obviously warrants further clinical studies. VP actions are all directed towards protecting homeostasis of the individual (water retention, blood pressure regulation, increased arousal and memory, etc), whereas OT actions are all directed towards maintenance of the social group (fetal expulsion, milking let down, sexual behaviour (Anderson-Hunt and Dennerstein, 1994), and social interactions (Insel, 1992) (still to be demonstrated in humans). Therefore it is tempting to see VP as a “selfish” and OT as an “altruistic” peptide (Legros, 1994). Such an integrative ago-antagonist, or “ying–yang”, action was postulated earlier for central VP and OT function in the rat (Engelman et al., 2000) and for the DHEAcortisol couple in humans (Nunez and Christeff, 1997). Hopefully future psychoneuroendocrine research will bring new insights on the mode of action of OT and the value of using its anti-stress properties in therapy. 5. Note added in proof While this Viewpoint was in press, Janet Amico presented oral data showing that oxytocin-knock out mice shown an ACTH-corticol response much more pronounced than normal mice during a “shaker stress” thus suggesting an inhibitory action of OT on ACTH-cortisol axis in mice also. Acknowledgements I wish to thank all the friends and collaborators who helped me in my work these 20 last years among whom: Profs Paolo Chiodera (Parma), Vincent Geenen, Marc
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Ansseau, Jean Claude Hendrick (Lie`ge), Martine Timsit-Berthier (PhD), Marion Crasson (PhD, Lie`ge) as well as Francine Louis and Marie-The´ re`se Hagelstein (Lie`ge) and many others! Most of the personal works cited here were supported by grants from the Belgian FNRS. References Altemus, M., 1995. Neuropeptides in anxiety disorders: effect of lactation. Ann. N.Y. Acad. Sci. 771, 697–707. Amico, J.A., Johnston, J.M., Vagnucci, A.H., 1994. Suckling-induced attenuation of plasma cortisol concentrations in post-partum lactating women. Endocr. Res. 20, 79–87. Anderson-Hunt, M., Dennerstein, L., 1994. Increased female sexual response after oxytocin. Brit. Med. J. 309, 929. Bohus, B., Kovacks, G.L., De Wied, D., 1978. Oxytocin, vasopressin and memory: opposite effects on consolidation and retrieval process. Brain Res. 157, 414–417. Chan, W.Y., Wo, N.C., Stoev, S., Cheng, L.L., Maning, M., 2000. Discovery and design of novel and selective vasopressin and oxytocin agonists and antagonists: the role of bioassays. Exp. Physiol. 85S, 7S–18S. Chiodera, P., Legros, J.J., 1981. L’injection intraveineuse d’ocytocine entraıˆne une diminution de la concentration plasmatique de cortisol chez l’homme normal. C.R. Soc. Biol. (Paris) 175, 546–549. Chiodera, P., Coiro, P., 1987. Oxytocin reduces metyrapone-induced ACTH secretion in human subjects. Brain Res. 420, 178–182. Chiodera, P., Salvarani, C., Bacchi-Modena, A., Spallanzani, R., Cigarini, C., Alboni, A., Gardini, E., Coiro, V., 1991. Relationship between plasma profiles of oxytocin and adre´ nocorticotropic hormone during suckling or breast stimulation in women. Horm. Res. 35, 119–123. Coiro, V., Passeri, M., Davoli, C., Bacchi-Modena, A., Bianconi, L., Volpi, R., Chiodera, P., 1988. Oxytocin reduces exercise induced ACTH and cortisol rise in man. Acta Endocrinologica (Kbh) 119, 405–412. Crine, A.F., Louis, F., Sulon, J., Legros, J.J., 1983. Changes in total serum immunoreactive neurophysins and corticosterone levels after restraint stress in rats. Psychoneuroendocrinology 8, 447–450. Degoeij, D.C.E., Dijkstra, H., Tilders, F.H.J., 1992. Chronic psychological stress enhances vasopressin but not corticotropin-releasing factor in the external zone of the median eminence of male rats: relationship to subordonate status. Endocrinology 131, 847–853. De Wied, D., 1965. The influence of the posterior and intermediate lobe of the pituitary and the pituitary peptides on the maintenance of a conditioned avoidance response in rats. Int. J. Neuropharmacol. 4, 157–167. Engelman, M., Wotjak, C.T., Ebner, K., Landcraf, R., 2000. Behavioral impact of intraseptally released vasopressin and oxytocin in rats. Exp. Physiol. 855, 125S–130S. Evans, J.J., 1997. Oxytocin in the human. Regulation of derivations and destinations. Eur. J. Endocrinol. 137, 559–571. Geenen, V., Adam, F., Baro, V., Mantanus, H., Ansseau, M., Timsit-Berthier, M., Legros, J.J., 1988. Inhibitory influence of oxytocin infusion on contingent negative variation and some memory tasks in normal men. Psychoneuroendocrinology 13, 367–375. Gibbs, D.M., 1985. High concentrations of oxytocin in hypophyseal portal plasma. Endocrinology 124, 1216–1218. Gibbs, D., 1986. Oxytocin inhibits ACTH and peripheral catecholamine secretion in the urethane-anesthetized rat. Regul. Pept. 14, 125–132. Gillies, G.E., Linton, E.A., Lowry, P.J., 1982. Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin. Nature 299, 355–357. Hary, L., Dupouy, J.E., Chatelain, A., 1993. ACTH secretion from isolated hypophyseal anterior lobes of male and female newborn rats: effects of corticotrophin-releasing factor, arginine-vasopressin and oxytocin alone or in combination. J. Endocrinol. 137, 123–132.
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Heinrichs, M., Meinlschmidt, G., Wagner, S., Simbrig, I., Wippich, W., Hellhammer, D.H., 1998. Selective effects of oxytocin on human memory. Psychoneuroendocrinology 23 (1), 15. Heinrichs, M., Meinlschmidt, G., Wagner, S., Neumann, I., Ehlert, U., Kirschbaum, C., Hellhamer, D.H., 2000. Breast feeding as a paradigm of social attachment: does it suppress psychoendocrine response to psychosocial stress in lactating women? J. Psychosom. Res. 48, 213–214. Holsboer, F., 1988. Implications of altered limbic–hypothalamic–pituitary–adrenocortical (LHPA)-function for neurobiology of depression. Acta Psychiatr. Scand. S341, S72–S111. Insel, T.R., 1992. Oxytocin- A neuropeptide for affiliation: evidence from behavioral, receptor, autoradiographic and comparative studies. Psychoneuroendocrinology 17, 3–35. Jezova, D., Skultetyova, I., Tokarev, D.I., Bakos, P., Vigas, M., 1995. Vasopressin and oxytocin in stress. Ann. N.Y. Acad. Sci. 771, 192–203. Jodogne, C., Tirelli, E., Klingbiel, P., Legros, J.J., 1991. Oxytocin attenuates tolerance not only to hypothermic but also to the myorelaxant and akinesic effects of ethanol in mice. Pharmacol. Biochem. Behavior 40, 261–265. Kovacs, G.L., Sarnyai, Z., Szabo, G., 1998. Oxytocin and addiction: a review. Psychoneuroendocrinology 23, 945–962. Legros, J.J., 1994. La longue marche des peptides neurohypophysaires. Acta Psychiatr. Belg. 94, 248–255. Legros, J.J., Franchimont, P., 1972. Human neurophysin blood level under normal, experimental and pathological conditions. Clin. Endocrinol. 1, 99–113. Legros, J.J., Grau, J.D., 1973. Influence of ethinyl-estradiol on neurohypophyseal content and release of immunoreactive vasopressin, oxytocin and neurophysin and of bio-assayable hormone in the rat. Nature (New Biology) 241, 247–249. Legros, J.J., Demoulin, A., Franchimont, P., 1975. Influence of chlorpromazine on positive and negative feedback mechanism of estrogens in man. Psychoneuroendocrinology 1, 185–198. Legros, J.J., Gilot, P., Seron, X., Claessens, J., Adam, A., Moeglen, J.M., Audibert, A., Berchier, P., 1978. Influence of vasopressin on learning and memory. Lancet 1, 41–42. Legros, J.J., Charles, G., Meunier, J.C., Smitz, S., Mendlewicz, J., 1982a. Neurophysins and cortisol levels during dexamethasone suppression test in depression. Neuroendocrinol. Lett. 4, 295–298. Legros, J.J., Louis, F., Chiodera, P., 1982b. Concomitant increase of neurophysin I and ACTH during insulin tolerance test in one out of five normal volunteers: influence of psychological stress? Neuroendocrinol. Lett. 4, 367–375. Legros, J.J., Chiodera, P., Demey-Ponsart, E., 1982c. Inhibitory influence of exogenous oxytocin on adenocorticotropin secretion in normal human subjects. J. Clin. Endocrinol. Metab. 55, 1035–1039. Legros, J.J., Deconinck, I., Willems, D., Roth, B., Pelc, O., Brauman, J., Verbanck, M., 1983a. Increase of neurophysin II serum levels in chronic alcoholic patients: relationship with alcohol consumption and alcoholism blood markers during withdrawal therapy. J. Clin. Endocrinol. Metab. 56, 871–875. Legros, J.J., Ansseau, M., Doumont, A., Crine, A.F., Geenen, V., Smitz, S., Charles, G., Demey-Ponsart, E., Sulon, J., Mens, W.B., Van Wimersma Greidanus, T.B.J., 1983b. Relationship between vasopressin, neurophysin and ACTH, cortisol plasma levels in non suppressor patients during dexamethasone suppression test. Neuroendocrinol. Lett. 5, 297–302. Legros, J.J., Chiodera, P., Geenen, V., Smitz, S., Von Franckell, R., 1984. Dose-response relationship between plasma oxytocin and cortisol and adrenocorticotropin concentrations during oxytocin infusion in normal men. J. Clin. Endocrinol. Metab. 58, 105–109. Legros, J.J., Chiodera, P., Geenen, V., Von Frenckell, R., 1987. Confirmation of the inhibitory influence of exogenous oxytocin on cortisol and ACTH in man: evidence of reproducibility. Acta Endocrinologica (Kbh) 114, 345–349. Legros, J.J., Chiodera, P., Geenen, V., 1988. Inhibitory action of exogenous oxytocin on plasma cortisol in normal human subjects: evidence of action at the adrenal level. Neuroendocrinology 48, 204–206. Legros, J.J., Boudarene, M., Timsit-Berthier, M., Hendrick, J.C., Crasson, M., Petraglia, F., 2000. AVPneurophysin but not AVP, nor CRF, is implicated in cortisol response to psychological stress in anxious healthy humans. Neuropsychopharmacology 23, S50. Lewis, D., Sherman, B., 1985. Oxytocin does not influence adrenocorticotropin secretion in man. J. Clin. Endocrinol. Metab. 60, 53–56. Lightman, S.L., Young, W.S., 1989. Lactation inhibit stress-mediated secretion of corticosterone and
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oxytocin and hypothalamic accumulation of corticotrophin-releasing factor and enkephalin messenger ribonucleic acids. Endocrinology 124, 2358–2364. Makara, G.B., Kiss, A., Lolait, S.J., Aguilera, G., 1996. Hypothalamic–pituitary corticotrop function after shunting of magnocellular vasopressin and oxytocin to the hypophyseal portal circulation. Endocrinology 137, 580–586. McCann, S.M., 1957. The ACTH-releasing activity of extracts of the posterior lobe of the pituitary (in vivo). Endocrinology 60, 664–676. McCarthy, M.M., 1995. Estrogen modulation of oxytocin and its relation to behavior. In: Ivell, R., Russel, J. (Eds.) Oxytocin. Plenum Press, New York, pp. 235–245. Nunez, E.A., Christeff, N., 1997. What are ago-antagonist couples? Their role in normal and pathological situations. Therapeutic consequences. Psychoneuroendocrinology 22, S95–S101. Petersson, M., Alster, P., Lundeberg, T., Uvnas-Moberg, K., 1996. Oxytocin causes a long-term decrease of blood pressure in female and male rats. Physiol. Behav. 60, 1311–1315. Petersson, M., Hulting, A.L., Uvnas-Moberg, K., 1999. Oxytocin causes a sustained decrease in plasma levels of corticosterone in rats. Neurosci. Lett. 264, 41–44. Petraglia, F., Facchinetti, F., D’Ambrogio, G., Volpe, A., Genazzani, R., 1986. Somatostatin and oxytocin infusion inhibits the rise of plasma β-endorphin, β-lipotropin and cortisol induced by insulin hypoglycaemia. Clin. Endocrinol. 24, 609–616. Romero, L.M., Levine, S., Sapolsky, R., 1995. Patterns of adrenocorticotropin secretagog release in response to social interactions and various degree of novelty. Psychoneuroendocrinology 20, 183–191. Schlosser, S.F., Almeida, O.F., Patchev, V.K., Yassouradis, A., Elands, J., 1994. Oxytocin-stimulated release of adrenocorticotropin from the rat pituitary is mediated by arginine vasopressin receptor of the V1b type. Endocrinology 135, 2058–2063. Scott, L.V., Dinan, T.G., 1998. Vasopressin and the regulation of hypothalamic–pituitary–adrenal axis function: implications for the pathophysiology of depression (Mini review). Life Sci. 62, 1985–1998. Stachowiak, A., Macchi, C., Nussdorfer, G.G., Malendowicz, 1995. Effects of oxytocin on the function and morphology of the rat adrenal cortex: in vitro and in vivo investigations. Res. Exp. Med. 195, 265–274. Suh, B.Y., Liu, J.H., Rasmussen, D.D., Gibbs, D.M., Steinberg, J., Yen, S.S.C., 1986. Role of oxytocin in the modulation of ACTH release in women. Neuroendocrinology 44, 309–313. Tirelli, E., Jodogne, C., Legros, J.J., 1992. Oxytocin blocks the environmentally conditioned compensatory response present after tolerance to ethanol-induced hypothermia in mice. Pharmacol. Biochem. Behavior 43, 1263–1267. Turner, R.A., Altemus, M., Enos, T., Cooper, B., McGuisness, T., 1999. Preliminary research on plasma oxytocin in normal cycling women: investigating emotion and interpersonal distress. Psychiatry 62, 97–113. Uvnas-Moberg, K., Windstrom, A.M., Nissen, E., Bjorvell, H., 1990. Personality traits in women 4 days postpartum and their correlation with plasma levels of oxytocin and prolactin. J. Psychosom. Obstet. Gynecol. 11, 261–273. Uvnas-Moberg, K., Bjorkstrand, E., Hillegaart, V., Althenius, S., 1999. Oxytocin as a possible mediator of SSRI-induced antidepressant effects. Psychopharmacology 142, 95–101. Vale, W., Spiess, J., Rivier, C., Rivier, J., 1981. Characterization of a 41-residue ovine hypothalamic peptide that stimulates the secretion of corticotropin and β-endorphin. Science 213, 1394–1397. Volpi, R., Chiodera, P., Bianconi, L., Marcato, A., Cavazzini, U., Pignatti, D., Capretti, L., Lacroce, P., Rossi, G., Camellini, L., Passeri, M., Coiro, V., 1989. Oxytocin does not modify glucagon- or calcitonin-induced ACTH-cortisol rise in humans. Horm. Metab. Res. 21, 635–637. Whithall, M.H., 1989. Stress selectively activates the vasopressin-containing subset of corticotropin-releasing hormone neurons. Neuroendocrinology 53, 150–159.
Viewpoint
Inhibitory effect of oxytocin on corticotrope function in humans: are vasopressin and oxytocin ying–yang neurohormones? Jean-Jacques Legros
*
Endocrine Service, Psychoneuroendocrine Unit, University of Liege — Sart Tilman, 4000 Lie`ge, Belgium Received 30 November 2000; received in revised form 18 March 2001; accepted 19 March 2001
Abstract Oxytocin (OT) and vasopressin (VP) are very similar neurohypophyseal peptides. While VP is known as an ACTH stimulating factor synergistic to CRF since two decades, the inhibiting activity of OT, first demonstrated in the human, is now confirmed in various species including mouse and rat! It is likely that endogenous oxytocinergic system which can be activated by physiological and/or pharmacological manipulation can “buffer” the stress activated vasopressin-ACTHcortisol action. Since VP and OT share also opposite action on cognitive function, those two “sister” neuropeptides might be considered as “ago-antagonist” or “ying–yang” neurohormones! 2001 Elsevier Science Ltd. All rights reserved. Keywords: Oxytocin; Vasopressin; Adrenals; Stress
1. Historical perspective It is well known that the hypothalamus exerts a stimulatory action on the release of ACTH and cortisol that is mediated by corticotropin releasing hormone (CRH) first isolated in 1981 by Vale and co-workers (Vale et al., 1981). However, decades
* Tel.: +32-4-366-8226; fax: 32-4-366-7261. E-mail address: [email protected] (J.-J. Legros). 0306-4530/01/$ - see front matter 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 3 0 6 - 4 5 3 0 ( 0 1 ) 0 0 0 1 8 - X
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J.-J. Legros / Psychoneuroendocrinology 26 (2001) 649–655
before this discovery, vasopressin (VP) was shown to exert a positive effect on ACTH release in central diabetes insipidus (DI) rats (McCann, 1957) and was therefore considered as a putative corticotropin releasing factor (CRF) until the discovery by Vale. Later research demonstrated that VP acts on the adenohypophyseal cells through a specific calcium dependant receptor V1b (or sometimes V3) different from the kidney (V2) and vascular (V1a) receptors. The actions of VP and CRH are synergistic (Gillies et al., 1982). Further it has been shown that VP plays a specific role in the adrenal response to a neurogenic stress in the rat (Crine et al., 1983; Whithall, 1989; Degoeij et al., 1992). Such an action had been suspected in the human (Legros et al., 1982b) and it was suggested to be at least partly responsible for the dexamethasone non-suppression (or “escape”) that is observed in some depressive patients (Legros et al., 1982a; 1983b; Holsboer, 1988) see review in Scott and Dinan (1998). We have recently shown that peripheral plasma VP-neurophysin was elevated together with ACTH and cortisol after a 2 hour mild stress test in 10 out of 25 non depressed patients who scored high on the Spielberger state anxiety scale thus confirming the role played by the central vasopressinergic system in ACTH regulation during “psychological stress” in non-pathological conditions (Legros et al., 2000). Besides its action at the periphery and at the hypothalamo–hypophyseal level, VP was shown by de Wied (1965) to exert a positive effect on some forms of “memory” in the rat. Such a positive action on cognitive function was later confirmed in humans (Legros et al., 1978). In the same year, Bohus et al. (1978) presented in the rat, the first evidence that oxytocin (OT) the “sister” neurohormone of VP can share and have opposite effects to those of VP on cognitive function, suggesting therefore “agonist–antagonist” actions of the two hormones. Such an inhibitory action of OT on evoked potential and memory tests was later confirmed in humans (Geenen et al., 1988). Recently Heinrichs and co-workers convincingly demonstrated that OT exerts a general amnesic influence on explicit memory, irrespective of the words’ content, whereas the nonapeptide selectively impairs implicit conceptual memory retrieval for words with reproduction-related meaning (Heinrichs et al., 1998). Based on Bohus’ hypothesis, we postulated that OT could also act as an antagonist of VP on ACTH secretion. Available data in the rat generally used dosages 50 to 100 times higher for OT than for VP (Gibbs, 1986; Hary et al., 1993). However, recent work showed that a chronic administration of OT at more physiological doses (1 µg/kg, ICV) caused a sustained decrease in plasma levels of corticosterone in the rat, an action opposite to that of VP (Petersson et al., 1999).
2. Action of exogenous OT on corticotrope function in the human We first demonstrated that IV infusion of 2 IU of OT in six normal male volunteers induced a decrease in cortisol plasma level (Chiodera and Legros, 1981). Later, we demonstrated that this action was dose-dependent (Legros et al., 1984) and related to a decrease of ACTH, thus suggesting an action at the hypothalamo–hypophyseal level (Legros et al., 1982c). However, this inhibitory action was not confirmed in a
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study on four normal males (Lewis and Sherman, 1985). Careful inspection of these later data revealed, however, that two among the four volunteers were obese, a condition known to activate endogenous neuropituitary function (Legros and Franchimont, 1972) and to probably desensitise tissue receptors to low dose infusion of neurohypophyseal peptides. We later confirmed the reproducibility of the sensitivity of corticotrope function in repeated testing compared to placebo in four normal male volunteers; in this study, we also evidenced a “rebound” effect on ACTH and cortisol at the end of the perfusion (Legros et al., 1987). This action of exogenous OT was subsequently confirmed during exercise-induced ACTH and cortisol release (Coiro et al., 1988), during insulin hypoglycemia (Petraglia et al., 1986) and following metyrapone activation (Chiodera and Coiro, 1987) (reviewed in Evans, 1997). The specificity of this action was further demonstrated by the absence of action of exogenous OT on glucagon and calcitonin induced ACTH-cortisol rise in humans (Volpi et al., 1989). The mechanism of action of OT on ACTH release could be competition at the level of the V1b receptor, as suggested by the inhibition of the exogenous VP induced ACTH release in the human (Legros et al., 1982c). Further it was demonstrated, in the rat, that the stimulatory action of OT on ACTH release is mediated by V1b receptors (Schlosser et al., 1994). However, although portal OT concentrations are quite high in humans (Gibbs, 1985), binding capacity of OT to V1b receptor appears to be incompatible with a direct antagonist action of OT on VP receptors (Chan et al., 2000). A partial direct inhibitory action of OT on ACTH effect at the adrenal level has also been demonstrated in normal humans (Legros et al., 1988). Such an inhibitory action of OT on ACTH-induced corticosterone synthesis has been described in “in vitro” and “in vivo” investigations in the rat (Stachowiak et al., 1995). Since corticosterone is hypotensive in the rat, this effect of OT could partly explain the hypotensive influence of exogenous OT observed in the same species (Petersson et al., 1996).
3. Endogenous OT and corticotrop function in the human The first demonstration of a decrease in corticosterone production during an oxytocin mediated process (lactation) was provided by Lightman and Young (1989) in the rat. Later, a relationship between endogenous OT release and corticotrope function was documented during various stresses in the same species (Jezova et al., 1995; Romero et al., 1995; Makara et al., 1996). In humans, the few studies that have been published investigated the simultaneous fluctuation of plasma ACTH and OT during nipple stimulation. Chiodera and coworkers showed an inverse relationship between plasma OT and ACTH levels during suckling in seven lactating women and during breast stimulation in six normally menstruating women (Suh et al., 1986; Chiodera et al., 1991). A similar relationship was confirmed in six breast feeding women by Amico et al. (1994), which is in agreement with an inhibitory influence of endogenous OT on ACTH/cortisol secretion in the very physiological conditions of nipple stimulation.
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4. OT as an endogenous anti-stress neuropeptide in humans In anxious mothers breast feeding is accompanied by relaxation and calm. The possibility that OT plays some role in the reduction of anxiety and/or stress during breast feeding is therefore worth considering (Uvnas-Moberg et al., 1990; Altemus, 1995; Heinrichs et al., 2000). With respect to this hypothesis, a recent study demonstrated that in 25 normal cycling women, a relaxing massage induced an increase in OT blood levels whereas imagery of sad emotions decreased OT (Turner et al., 1999). The same authors also reported that peripheral secretion of OT in response to emotional stimuli is associated with individuals’ interpersonal characteristics (Turner et al., 1999). If this inhibitory action of OT on adrenals is clinically relevant, then pharmacological activation of endogenous OT release by hormones (estrogens) (Legros and Grau, 1973; Legros et al., 1975; McCarthy, 1995) or a psychotropic agent like SSRI (Uvnas-Moberg et al., 1999) might be considered at least partially as a way of alleviating stress. It is also known that alcohol ingestion induces a release of OT-neurophysin in humans (Legros et al., 1983a) and that exogenous OT inhibits the development of tolerance to the incapacitating action of ethanol in rats (Jodogne et al., 1991; Tirelli et al., 1992). OT could then participate not only in the anxiolytic effect of ethanol but could also protect individuals against addiction to this anxiolytic effect (review in Kovacs et al., 1998), a possibility that obviously warrants further clinical studies. VP actions are all directed towards protecting homeostasis of the individual (water retention, blood pressure regulation, increased arousal and memory, etc), whereas OT actions are all directed towards maintenance of the social group (fetal expulsion, milking let down, sexual behaviour (Anderson-Hunt and Dennerstein, 1994), and social interactions (Insel, 1992) (still to be demonstrated in humans). Therefore it is tempting to see VP as a “selfish” and OT as an “altruistic” peptide (Legros, 1994). Such an integrative ago-antagonist, or “ying–yang”, action was postulated earlier for central VP and OT function in the rat (Engelman et al., 2000) and for the DHEAcortisol couple in humans (Nunez and Christeff, 1997). Hopefully future psychoneuroendocrine research will bring new insights on the mode of action of OT and the value of using its anti-stress properties in therapy. 5. Note added in proof While this Viewpoint was in press, Janet Amico presented oral data showing that oxytocin-knock out mice shown an ACTH-corticol response much more pronounced than normal mice during a “shaker stress” thus suggesting an inhibitory action of OT on ACTH-cortisol axis in mice also. Acknowledgements I wish to thank all the friends and collaborators who helped me in my work these 20 last years among whom: Profs Paolo Chiodera (Parma), Vincent Geenen, Marc
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Ansseau, Jean Claude Hendrick (Lie`ge), Martine Timsit-Berthier (PhD), Marion Crasson (PhD, Lie`ge) as well as Francine Louis and Marie-The´ re`se Hagelstein (Lie`ge) and many others! Most of the personal works cited here were supported by grants from the Belgian FNRS. References Altemus, M., 1995. Neuropeptides in anxiety disorders: effect of lactation. Ann. N.Y. Acad. Sci. 771, 697–707. Amico, J.A., Johnston, J.M., Vagnucci, A.H., 1994. Suckling-induced attenuation of plasma cortisol concentrations in post-partum lactating women. Endocr. Res. 20, 79–87. Anderson-Hunt, M., Dennerstein, L., 1994. Increased female sexual response after oxytocin. Brit. Med. J. 309, 929. Bohus, B., Kovacks, G.L., De Wied, D., 1978. Oxytocin, vasopressin and memory: opposite effects on consolidation and retrieval process. Brain Res. 157, 414–417. Chan, W.Y., Wo, N.C., Stoev, S., Cheng, L.L., Maning, M., 2000. Discovery and design of novel and selective vasopressin and oxytocin agonists and antagonists: the role of bioassays. Exp. Physiol. 85S, 7S–18S. Chiodera, P., Legros, J.J., 1981. L’injection intraveineuse d’ocytocine entraıˆne une diminution de la concentration plasmatique de cortisol chez l’homme normal. C.R. Soc. Biol. (Paris) 175, 546–549. Chiodera, P., Coiro, P., 1987. Oxytocin reduces metyrapone-induced ACTH secretion in human subjects. Brain Res. 420, 178–182. Chiodera, P., Salvarani, C., Bacchi-Modena, A., Spallanzani, R., Cigarini, C., Alboni, A., Gardini, E., Coiro, V., 1991. Relationship between plasma profiles of oxytocin and adre´ nocorticotropic hormone during suckling or breast stimulation in women. Horm. Res. 35, 119–123. Coiro, V., Passeri, M., Davoli, C., Bacchi-Modena, A., Bianconi, L., Volpi, R., Chiodera, P., 1988. Oxytocin reduces exercise induced ACTH and cortisol rise in man. Acta Endocrinologica (Kbh) 119, 405–412. Crine, A.F., Louis, F., Sulon, J., Legros, J.J., 1983. Changes in total serum immunoreactive neurophysins and corticosterone levels after restraint stress in rats. Psychoneuroendocrinology 8, 447–450. Degoeij, D.C.E., Dijkstra, H., Tilders, F.H.J., 1992. Chronic psychological stress enhances vasopressin but not corticotropin-releasing factor in the external zone of the median eminence of male rats: relationship to subordonate status. Endocrinology 131, 847–853. De Wied, D., 1965. The influence of the posterior and intermediate lobe of the pituitary and the pituitary peptides on the maintenance of a conditioned avoidance response in rats. Int. J. Neuropharmacol. 4, 157–167. Engelman, M., Wotjak, C.T., Ebner, K., Landcraf, R., 2000. Behavioral impact of intraseptally released vasopressin and oxytocin in rats. Exp. Physiol. 855, 125S–130S. Evans, J.J., 1997. Oxytocin in the human. Regulation of derivations and destinations. Eur. J. Endocrinol. 137, 559–571. Geenen, V., Adam, F., Baro, V., Mantanus, H., Ansseau, M., Timsit-Berthier, M., Legros, J.J., 1988. Inhibitory influence of oxytocin infusion on contingent negative variation and some memory tasks in normal men. Psychoneuroendocrinology 13, 367–375. Gibbs, D.M., 1985. High concentrations of oxytocin in hypophyseal portal plasma. Endocrinology 124, 1216–1218. Gibbs, D., 1986. Oxytocin inhibits ACTH and peripheral catecholamine secretion in the urethane-anesthetized rat. Regul. Pept. 14, 125–132. Gillies, G.E., Linton, E.A., Lowry, P.J., 1982. Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin. Nature 299, 355–357. Hary, L., Dupouy, J.E., Chatelain, A., 1993. ACTH secretion from isolated hypophyseal anterior lobes of male and female newborn rats: effects of corticotrophin-releasing factor, arginine-vasopressin and oxytocin alone or in combination. J. Endocrinol. 137, 123–132.
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