J. Anat.

(2005) 207, pp259264

Blackwell Publishing, Ltd.

REVIEW

Anatomy of melancholia: focus on hypothalamic pituitaryadrenal axis overactivity and the role of vasopressin
Timothy G. Dinan and Lucinda V. Scott
Department of Psychiatry and Alimentary Pharmabiotic Centre, Cork University Hospital, Ireland

Abstract
Overactivity of the hypothalamicpituitaryadrenal (HPA) axis characterized by hypercortisolism, adrenal hyperplasia and abnormalities in negative feedback is the most consistently described biological abnormality in melancholic depression. Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are the main secretagogues of the HPA/stress system. Produced in the parvicellular division of the hypothalamic paraventricular nucleus the release of these peptides is influenced by inputs from monoaminergic neurones. In depression, anterior pituitary CRH1 receptors are down-regulated and response to CRH infusion is blunted. By contrast, vasopressin V3 receptors on the anterior pituitary show enhanced response to AVP stimulation and this enhancement plays a key role in maintaining HPA overactivity. Key words ACTH; cortisol; hypothalamus; stress; vasopressin.

Introduction
Melancholic depression is a common, severe medical condition characterized by low mood, anhedonia, sleep and appetite disturbance, low self-esteem and poor concentration. The most consistently demonstrated biological abnormality in melancholia is overactivity of the hypothalamicpituitaryadrenal (HPA) axis characterized by hypercortisolism, adrenal hyperplasia and abnormalities in negative feedback (Rubin et al. 2001). The HPA is the core endocrine stress system, the activation of which is essential in providing an appropriate biological response to stress. Failure to activate the axis in response to chronic stress is incompatible with life as evidenced by Addisons disease, a disorder caused by the inability to elevate cortisol. The HPA abnormality in depression is akin to a sustained stress response following removal of the stressor. The classic monoamine neurotransmitters projecting to the hypothalamus provide important regulation of

HPA activity. Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are the major secretagogue peptides of the HPA / stress system. CRH is a 41 amino acid peptide, originally discovered and sequenced by Vale et al. (1981). It is produced in the medial parvicellular division of the paraventricular nucleus (PVN) of the hypothalamus. These neurones project to the external zone of the median eminence, where CRH is released into the portal vasculature to act on CRH1 receptors at the anterior pituitary. CRH and AVP act synergistically in bringing about adrenocorticotropin (ACTH) release from the corticotropes of the anterior pituitary, which in turn stimulates cortisol output from the adrenal cortex. Following its identification in 1954, AVP, a nonapeptide, was considered the principal factor in the regulation of ACTH release until the subsequent elucidation of the structure of CRH. At that point CRH became the main focus of attention. This dominance has certainly been reflected in recent neuroendocrine studies conducted in depression.

Correspondence Professor Timothy Dinan, Department of Psychiatry and Alimentary Pharmabiotic Centre, Cork University Hospital, Wilton, Cork, Ireland. T: +353 21 490 1224; F: +353 21 492 2584; E: t.dinan@ucc.ie. Accepted for publication 9 June 2005 Anatomical Society of Great Britain and Ireland 2005

AVP distribution
AVP is released following a variety of stimuli including increasing plasma osmolality, hypovolaemia, hypotension

260 Hypothalamicpituitaryadrenal axis, T. G. Dinan and L. V. Scott

and hypoglycaemia. It has powerful anti-diuretic and vasoconstrictor effects (Robertson, 1992). Our knowledge of the functional anatomy and pharmacology of AVP and its receptors in the regulation of HPA activity rests largely on studies conducted in rodents. AVP is released from the magnocellular system and from the parvicellular neurones of the PVN. AVP produced by the latter neurones is secreted into the pituitary portal circulation from axon terminals projecting to the external zone of the median eminence (Antoni, 1993). AVPcontaining cell bodies in the PVN are co-localized with CRH-containing neurones. In control non-stressed rats, within the pool of CRH neurosecretory cells, 50% coexpress AVP (Whitnall, 1987). CRH+/AVP neurones are mostly found medially and ventrally, whereas CRH+/ AVP+ cells are located more dorsally and laterally in the PVN. The neurosecretory granules in CRH neurones undergo remarkable changes in size and peptide composition under experimental manipulations of the HPA axis. For example, after adrenalectomy the number of CRH+/AVP+ cells in the hypothalamic PVN increases; a similar shift towards AVP production in parvicellular neurones appears after various types of chronic stress (De Goeij et al. 1992). Based on the observation that in mice all CRH-immunopositive nerve endings contain AVP, Antoni (1993) suggests that in rats all CRH axon terminals express varying levels of AVP, but that low levels of AVP elude detection. In humans there is evidence also that all CRH neurones in the hypothalamus may contain AVP (Mouri et al. 1993). The PVN serves as an important relay site. It receives projections from ascending catecholaminergic pathways including noradrenergic projections from the nucleus of the solitary tract and from the locus coeruleus. It also receives input from areas of the limbic system, notably the bed nucleus of the stria terminalis, the hippocampus and amygdala. In primates, including humans, high levels of immunoreactive AVP neurones have been demonstrated in these areas and also in the pituitary intermediate lobe, granular layers of the cerebellum and dentate gyrus. Lower levels are found in the medial habenula, adenohypophysis, area postrema, pineal, subfornical and subcommisural organs. It is thought that the bulk of AVP in the portal vasculature derives from the PVN but morphological and neurochemical studies suggest that AVP from supraoptic magnocellular AVP-secreting cells also access the hypophyseal portal blood (Antoni et al. 1990).

Vasopressin receptors
As with other peptide hormones AVP exerts its effects through interaction with specific plasma membrane receptors of which three major subtypes have been identified (Jard et al. 1987; Birnbaumer, 2000). V1a receptors are widely distributed on blood vessels, and have also been found in the CNS, including the PVN (Tribollet et al. 1992). V2 receptors are predominantly located in the principal cells of the renal collecting system, although there is some evidence for central V2 receptors also. The ACTH-releasing properties occur via the V3 (V1b) receptor subtype. The renal V2 receptors are linked to adenylate cyclase, whilst V1 receptors are cAMP dependent and are coupled to calcium phospholipiddependent signalling systems. Both pharmacological and molecular cloning studies support the difference between the subtypes. In situ hybridization studies reveal that V3 receptor mRNA is expressed in the majority of pituitary corticotropes, in multiple brain regions and a number of peripheral tissues including kidney, heart, lung and breast and adrenal medulla (Grazzini et al. 1996).

CRH and AVP interaction

Vasopressin has ACTH-releasing properties when administered alone in humans (Salata et al. 1988), a response which may be dependent on the ambient endogenous CRH level. Following the combination of AVP and CRH, a much greater synergistic ACTH response is seen (Favrod-Coune et al. 1993), and both peptides are required for maximal pituitaryadrenal stimulation (De Bold et al. 1984). The precise nature of this synergism is incompletely understood, with most information deriving from animal studies. It has been demonstrated that CRH, through cAMP, increases pro-opiomelanocortin (POMC) gene transcription and peptide synthesis and storage. There may also be distinct corticotrope populations in the anterior pituitary, some of which require both AVP and CRH for ACTH release (Jia et al. 1991). Antoni (1993) suggests that AVP plays a role in stimulating the primary nuclear transcripts induced by CRH at the pituitary corticotrope.

CRH and AVP regulation by glucocorticoids

Glucocorticoids play a pivotal feedback role in the regulation of the HPA (Keller-Wood & Dallman, 1984).
Anatomical Society of Great Britain and Ireland 2005

Hypothalamicpituitaryadrenal axis, T. G. Dinan and L. V. Scott 261

Two types of cortisol binding sites have been described in the brain. The type 1 receptor, which is indistinguishable from the peripheral mineralocorticoid receptor, is distributed principally in the septo-hippocampal region (Chao et al. 1989). The type 2 or glucocorticoid receptor has a wider distribution. These receptor systems provide negative feedback loops at a limbic, hypothalamic and pituitary level. Overall the type 1 receptor is thought to mediate tonic influences of cortisol or corticosterone, whereas the type 2 receptor mediates stress-related changes in cortisol levels. Under normal conditions the responsiveness of parvicellular neurones to stress is under marked inhibition by the low resting levels of glucocorticoids. The sensitivity of CRH and AVP transcription to glucocorticoid feedback is markedly different (Ma et al. 1999). CRH mRNA and CRH 1 receptor mRNA levels are reduced by elevated glucocorticoids (Zhou et al. 1996), whereas V3 receptor mRNA levels and coupling of the receptor to phospholipase C are stimulated by glucocorticoids, effects which may contribute to the refractoriness of AVP-stimulated ACTH secretion to glucocorticoid feedback (Aguilera & Rabadan-Diehl, 2000). This suggests that vasopressinergic regulation of the HPA axis is critical for sustaining corticotrope responsiveness in the presence of high circulating glucocorticoid levels during chronic stress.

rats, which lack hypothalamic AVP, show only a minor reduction in CRH receptor number which was augmented by AVP in the post-adrenalectomy period. Repeated immobilization stress (and repeated hypertonic saline injections) was found to bring about sustained elevations in V3 receptor mRNA in the pituitary (Rabadan-Diehl et al. 1995), suggesting an up-regulation of AVP receptors in situations of chronic stress. This may explain the preserved enhanced response to novel superimposed stress in these animal models. These findings support Plotskys (1991) original proposal that CRH plays a predominantly permissive role in HPA regulation but that AVP represents the dynamic mediator of ACTH release.

Vasopressin in major depression

Studies of HPA function in depression reveal numerous abnormalities. These abnormalities are most pronounced in depressives with melancholic features (Dinan, 1994). A role for AVP is supported by dynamic tests of HPA activity, in particular, the DEX/CRH test. Dexamethasone (DEX), a potent synthetic glucocorticoid, binds primarily to glucocorticoid receptors on anterior pituitary corticotropes and, by feedback inhibition, suppresses ACTH and cortisol secretion (Cole et al. 2000). In the DEX/CRH test, when healthy subjects are treated with dexamethasone prior to CRH infusion, the release of ACTH is blunted and the extent of blunting is proportional to the dose of DEX (von Bardeleben & Holsboer, 1989). Paradoxically, when depressives are pretreated with DEX they show an enhanced ACTH response to CRH. It was postulated that AVP-mediated ACTH release was responsible for this finding. The combined DEX /CRH test is estimated to have a sensitivity of 80% in differentiating healthy subjects from depressives (Heuser et al. 1994). Several groups have used vasopressin-mediated cortisol output as a means of assessing HPA function in depressive disorders (Jakobsen et al. 1969; Carroll, 1972; Krahn et al. 1985). Although suggestive of an abnormal cortisol response to vasopressin administration, the results are difficult to interpret; two of the studies were uncontrolled and utilized lysine vasopressin, which causes significant adverse side-effects, and the third (Krahn et al. 1985), although controlled, used small numbers and a submaximal dose of AVP. Meller et al. (1987), based on data that supported chronic hypersecretion of CRH in depression and subsequent

Effects of chronic stress on CRH/AVP

Immobilization stress and the use of hierarchically structured colonies both function as psychological stress paradigms. Studies employing these paradigms in rats reveal a shift of the hypothalamic CRH/AVP signal in favour of AVP; there is enhanced AVP synthesis in CRH-producing cells of the parvicellular neurones of the PVN and AVP storage in the CRH-containing nerve terminals in the external zone of the median eminence. An increased proportion of hypothalamic neurones co-expressing AVP is also observed. By contrast, CRH production remains unaltered or decreased (De Goeij et al. 1992). A similar pattern of response is seen following prolonged immobilization stress, in which a shift towards an increased AVP/CRH ratio is observed (Whitnall, 1989). Direct manipulations of the HPA axis reinforce this idea. Tizabi & Aguilera (1992), using a minipump infusion of CRH, revealed a reduction in CRH receptor number which was enhanced by the simultaneous infusion of AVP, whereas adrenalectomized Battleboro
Anatomical Society of Great Britain and Ireland 2005

262 Hypothalamicpituitaryadrenal axis, T. G. Dinan and L. V. Scott

down-regulation of pituitary CRH receptors as the key biological abnormality in major depressive disorder, hypothesized that AVP, which stimulates specific receptors unattenuated by CRH levels, would cause normal release of ACTH and subsequent increased release of cortisol from chronically stimulated and hyper-responsive adrenals. Twenty-seven subjects with major depression or bipolar disorder (of depressed type) underwent AVP infusion; the depressed cohort released significantly greater cortisol than the control population and ACTH response was similar in the two groups. Again, on comparing depressed and healthy subjects, Kathol et al. (1989) found a blunted ACTH response to ovine CRH administration in the depressed group, whereas following AVP administration there was only a non-significant trend towards a reduction in ACTH release. In the studies by Kathol et al. (1989) and Meller et al. (1987), depressed patients had nonsignificantly greater cortisol production. Dinan et al. (1999) examined a cohort of depressed subjects on two separate occasions, with CRH alone, and with the combination of CRH and ddAVP (desmopressin). A significant blunting of ACTH output to CRH alone was noted. Following the combination of CRH and ddAVP, the release of ACTH in depressives and healthy volunteers was indistinguishable. It was concluded that although the CRH1 receptor is downregulated in depression, a concomitant up-regulation of the V3 receptor takes place. This is consistent with the animal models of chronic stress, described above, in which a switching from CRH to AVP regulation is observed. It is interesting that in CRH1 receptor-deficient mice, basal plasma AVP levels are significantly elevated, AVP mRNA is increased in the PVN and there is increased AVP-like immunoreactivity in the median eminence (Muller et al. 2000). In a recent study we have provided further evidence for the up-regulation of the anterior pituitary V3 receptor (Dinan et al. 2004). Fourteen patients with major depression and 14 age- and sex-matched healthy controls were recruited. ddAVP (10 g) was given intravenously and ACTH and cortisol release were monitored for 120 min. The mean SEM ACTH response was 28.4 4.3 ng L1 in the depressives and 18.8 4.9 ng L1 (P = 0.04) in the healthy subjects. The mean SEM cortisol response was 261.8 46.5 nmol L1 in the depressives and 107.3 26.1 nmol L1 in the healthy subjects (P < 0.01). This suggests that patients with major depression have

augmented ACTH and cortisol responses to ddAVP, indicating enhanced V3 responsivity.

Basal measures and symptom profile

There are relatively few data on plasma AVP levels in depression. An early report found no change in plasma AVP levels in depression (Gjerris et al. 1985). By contrast, Van Londen et al. (1997) reported basal plasma levels of AVP to be elevated. In this study 52 major depressives and 37 healthy controls were compared; AVP concentrations were found to be higher in the depressed cohort, with greater elevation in in-patient compared with out-patient depressives and in those with melancholic features. A number of studies have shown a significant positive correlation between peripheral plasma levels of AVP and hypercortisolaemia in patients with unipolar depression (Van Londen et al. 1997; Inder et al. 1998). It has been postulated that increases in central noradrenergic activity causing activation of ACTH and cortisol secretion, mediated through CRH and AVP, may underlie the hypercortisolism seen in some depressed subjects (Liu et al. 1994).

Post-mortem studies
A post-mortem study of depressed subjects reported an increased number of vasopressin-expressing neurones in paraventricular hypothalamic neurones (Purba et al. 1996). Raadsheer et al. (1994) have also shown an increase in number of CRH-neurones in depressives.

Conclusions
The question arises as to what type of involvement AVP may have in HPA dysregulation in depressive illness. Is a change in AVP regulation a biological correlate, a component of aetiology or a response to another hormonal disequilibrium? Activation of the HPA axis in situations of stress is a normal homeostatic mechanism. In healthy subjects this response ceases when no longer biologically relevant. It is on this basis that we suggest an important role for AVP in the pathophysiology of major depression. Extrapolating from animal models of chronic stress, in which there is a switch from CRH to AVP regulation of ACTH release, a similar occurrence in humans is readily conceptualized. Supportive evidence includes the demonstration in depressed subjects of increased
Anatomical Society of Great Britain and Ireland 2005

Hypothalamicpituitaryadrenal axis, T. G. Dinan and L. V. Scott 263

numbers of CRH neurones in the PVN co-expressing AVP and the ability of ddAVP to normalize the blunting of CRH-induced ACTH release, suggesting pituitary V3 receptor up-regulation (Dinan et al. 1999). Of importance also is the relative refractoriness of AVP-stimulated ACTH release to circulating glucocorticoids (Aguilera & Rabadan-Diehl, 2000). This would suggest that in major depression, the constant forward drive of the HPA axis may depend on AVP activity unrestrained by elevated ambient cortisol levels. The switch in emphasis from CRH- to AVP-ergic pituitaryadrenal regulation in situations of chronic stress results in a continued activation of the HPA axis after the initial CRH-mediated response to stress is biologically appropriate. This recruitment of AVP as the primary regulator of the HPA axis in chronic stress conditions may explain the hypercortisolaemia that is demonstrated in depressed subjects, even when CRH / ACTH release is reduced, probably secondary to pituitary CRH receptor down-regulation.

References
Aguilera G, Rabadan-Diehl C (2000) Vasopressinergic regulation of the hypothalamicpituitaryadrenal axis: implications for stress adaptation. Regul Pept 96, 23 29. Antoni F, Fink G, Sheward W (1990) Corticotrophin-releasing peptides in rat hypophysial portal blood after paravedntricular lesions: a marked reduction in the concentration of 41-residue corticotropin-releasing factor, but no change in vasopressin. J Endocrinol 125, 175 183. Antoni FA (1993) Vasopressinergic control of pituitary-adrenal secretion comes of age. In Frontiers in Neuroendocrinology, pp. 76122. New York: Raven Press. Birnbaumer M (2000) Vasopressin receptors. Trends Endocrinol Metab 1, 406410. von Bardeleben U, Holsboer F (1989) Cortisol response to a combined dexamethasone-human corticotropin-releasing hormone challenge in patients with depression. J Neuroendocrinol 1, 485 488. Carroll BJ (1972) The hypothalamicc pituitary adrenal axis in depression. In Depressive Illness: Some Research Studies (eds Davies B, Carroll PW, Mowbray R), pp. 23 201. Springfield, IL: C C. Thomas. Chao HM, Choo P, McEwen B (1989) Glucocorticoid and mineralocorticoid receptor mRNA expression in the rat brain. Neuroendocrinology 50, 365 371. Cole MA, Kim PJ, Kalman BA, Spencer RL (2000) Dexamethasone suppression of cortciosteroid secretion: evaluation of the site of action by receptor measures and functional studies. Psychoneuroendocrinology 25, 151 167. De Bold CR, Sheldon WR, DeCherney GS, et al. (1984) Arginine vasopressin potentiates adrenocorticotropin release induced by ovine corticotropin-releasing factor. J Clin Invest 73, 533 538. De Goeij D, Djikstra H, Tilders F (1992) Chronic psychosocial
Anatomical Society of Great Britain and Ireland 2005

stress enhances vasopressin but not corticotropin-releasing factor, in the external zone of the median eminence of male rats: relationship to subordinate status. Endocrinology 131, 847 853. Dinan TG (1994) Glucocorticoids and the genesis of depressive illness: a psychobiological model. Br J Psychiatry 164, 365 371. Dinan TG, Lavelle E, Scott L, Medbak S, Grossman A (1999) Desmopressin normalises the blunted ACTH response to corticotropin-releasing hormone in melancholic depression: evidence of enhanced vasopressinergic responsivity. J Clin Endocrinol Metab 84, 2238 2246. Dinan TG, OBrien S, Lavelle E, Scott LV (2004) Further neuroendocrine evidence of enhanced V3 receptor responses in melancholic depression. Psychol Med 34, 169 172. Favrod-Coune C, Raux-Demay M, Proeschel M, Bertagna X, Girard F, Luton JP (1993) Potentiation of the classic ovine corticotropin-releasing hormone stimulation test by the combined administration of small doses of lysine vasopressin. Clin Endocrinol 38, 405 410. Gjerris A, Hammer M, Vendsborg P, Christensen NJ, Rafaelsen OJ (1985) Cerebrospinal fluid vasopressin changes in depression. Br J Psychiat 147, 696 701. Grazzini E, Lodboerer AM, Perez-Martin A, Joubert D, Guillon G (1996) Molecular and functional characterization of the V1b receptor in rat adrenal medulla. Endocrinology 137, 3906 3914. Heuser I, Yassouridis A, Holsboer F (1994) The combined dexamethasone / CRH test: a refined laboratory test for psychiatric disorders. J Affect Dis 4, 93 101. Inder WJ, Swanney MP, Donald RA, Prickett TC, Hellemans J (1998) The effect of glycerol and desmopressin on exercise performance and hydration in triathletes. Med Sci Sports Exerc 30, 1263 1269. Jakobsen T, Blomenthal M, Hagman H, Heikkinen E (1969) The diurnal variation of urinary and plasma 17-hydroxycorticosteroid (17-OHCS) levels and plasma 17-OHCS response to lysine-8-vasopressin in depressive patients. J Psychosom Res 13, 363 375. Jard S, Gaillard R, Guillon G, et al. (1987) Vasopressin receptor antagonists allow demonstration of a novel type of vasopressin receptor in the rat adenohypophysis. Molec Pharmacol 30, 171 180. Jia L-G, Canny B, Orth D, Leong D (1991) Distinct class of corticotropes mediate corticotropin-releasing hormone and arginine vasopressin-stimulated adrenocorticotropin release. Endocrinology 128, 197 203. Kathol R, Jaeckle R, Lopez J, Meller W (1989) Consistent reduction of ACTH responses to stimulation with CRH, vasopressin and hypoglycaemia in patients with major depression. Br J Psychiatry 155, 468 478. Keller-Wood M, Dallman M (1984) Corticosteroid inhibition of ACTH secretion. Endocr Rev 5, 123. Krahn DD, Meller WH, Shafer RB, Morley JE (1985) Cortisol response to vasopressin in depression. Biol Psychiatry 20, 918 921. Liu JP, Clarke IJ, Funder JW, Engler JD (1994) Studies of the secretion of corticotropin-releasing factor and arginine vasopressin into the hypophyseal-portal circulation of the conscious sheep. II. The central noradrenergic and

264 Hypothalamicpituitaryadrenal axis, T. G. Dinan and L. V. Scott

neuropeptide pathways cause immediate and prolonged hypothalamicpituitaryadrenal activation: potential involvement in the pseudo-Cushings syndrome of endogenous depression and anorexia nervosa. J Clin Invest 93, 1439 1450. Ma XM, Lightman S, Aguilera G (1999) Vasopressin and corticotropin-releasing hormone gene responses to novel stress in rats adapted to repeated restraint. Endocrinology 140, 36233632. Meller WH, Kathol RC, Jaeckle RS, Lopez JF (1987) Stimulation of the pituitary-adrenal axis with arginine vasopressin in patients with depression. J Psychiat Res 21, 269 277. Mouri T, Itoi K, Takahashi K, et al. (1993) Co-localization of corticotropin-releasing factor and vasopressin in the paraventricular nucleus of human hypothalamus. Neuroendocrinology 57, 34 39. Muller MB, Landgraf R, Keck M (2000) Vasopressin, major depression, and hypothalamic-pituitary-adenocortical desensitization. Biol Psychiatry 48, 330 333. Plotsky P (1991) Pathways to the secretion of adrenocortictropin: a view from the portal. J Neuroendocrinol 3, 1 9. Purba J, Hoogendijk W, Hoffman M, Swaab D (1996) Increased numbers of vasopressin- and oxytocin-containing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch Gen Psych 53, 137 143. Raadsheer FC, Hoogendijk WJG, Stam FC, Tilders FJH, Swaab DF (1994) Increased number of corticotropin-releasing hormone neurons in the hypothalamic paraventricular nuclei of depressed patients. Neuroendocrinology 60, 436 444. Rabadan-Diehl C, Lolait S, Aguilera G (1995) Regulation of the pituitary V1b receptor mRNA during stress in the rat. J Neuroendocrinol 7, 903 910. Robertson G (1992) In The Kidney: Pathophysiology and Pathophysiology , 2nd edn. (eds Selden D, Giebisch C), pp. 15951613. New York: Raven Press.

Rubin R, Dinan TG, Scott LV (2001) The neuroendocrinology of affective disorders. In Hormones, Brain and Behaviour (eds Pfaff D, Arnold AP, Etgen AM, Fahrbach SE, Moss RL, Rubin RT), pp. 467 514. New York: Academic Press. Salata RA, Jarrett DB, Verbalis JG, Robinson AG (1988) Vasopressin stimulation of adrenocorticotropin hormone (ACTH) in humans. In vivo bioassay of corticotropin-releasing factor (CRF) which provides evidence for CRF mediation of the diurnal rhythm of ACTH. J Clin Invest 81, 766 774. Tizabi Y, Aguilera G (1992) Desensitization of the hypothalamic pituitaryadrenal axis following prolonged administration of corticotropin-releasing hormone and vasopressin. Neuroendocrinology 56, 611 618. Tribollet E, Barberis C, Dubois-Dauphin M, Dreifuss JJ (1992) Localization and characterization of binding sites for vasopressin and oxytocin in the brain of the guinea pig. Brain Res 589, 15 23. Vale W, Spiess J, Rivier C, Rivier J (1981) Characterisation of a 41 residue ovine hypothalamic peptide that stimulates secretion of the corticotropin and beta-endorphin. Science 213, 1394 1399. Van Londen L, Goekoop J, van Kempen G, FrankhuijzenSierevogel A, Wiegant V, De Wied D (1997) Plasma levels of arginine vasopressin elevated in patients with major depression. Neuropsychopharmacology 17, 284 292. Whitnall M (1987) Vasopressin co-exists in half of the corticotropin-releasing factor neurones in the external zone of the median eminence in normal rats. Neuroendocrinology 45, 420 424. Whitnall M (1989) Stress selectively activates the vasopressincontaining subset of corticotropin-releasing hormone neurons. Neuroendocrinology 50, 702 707. Zhou JN, Hofman MA, Swaab DF (1996) Morphometric analysis of vasopressin and vasoactive intestinal polypeptide neurons in the human suprachiasmatic nucleus: influence of microwave treatment. Brain Res 742, 334 338.

Anatomical Society of Great Britain and Ireland 2005