In: G Fink, Editor in Chief,
Stress: Neuroendocrinology and Neurobiology
Vasopressin as a stress hormone
Ferenc A. Antoni
Division of Preclinical Research
Egis Pharmaceuticals PLC, Budapest , Hungary
Division of Preclinical Research
Egis Pharmaceuticals PLC, Budapest , Hungary
Mobile: +36 20 532 9520
Vasopressin is a small neuropeptide initially identified as the physiologically essential
antidiuretic hormone more than 50 years ago. Since then, it has increasingly
become apparent that vasopressin is an important hormonal component of the
response to stress. In fact, it appears that the antidiuretic effect is only one of
several biologically significant actions of vasopressin exerted during the response to
stress. This review highlights the main features of vasopressin as a stress hormone
produced by relatively simple hypothalamic neurons that release their
neurotransmitters into the blood stream and also send axonal projections to key parts
of the brain that control the response to stressful environmental challenges. Special
focus is on the role of vasopressin in : 1) setting the efficacy of adrenal corticosteroid
feedback inhibition; 2) the stress of pain ; and 3) supporting the response to
Corticotropin releasing-factor, HPA axis, vasopressin-receptors, intracellular
signaling, dexamethasone non-suppression, arthritis, autoimmune disorders,
interleukin-6, personalized medicine
Vasopressin-like peptides serve as hormones that preserve salt-water balance
already in invertebrates
This ancient trait is preserved in mammals and is part of the neuroendocrine
response to stress in which vasopressin plays a fundamental role.
The set-point of feedback inhibition by adrenal corticosteroids in the
hypothalamic-pituitary-adrenocortical axis is altered by vasopressin to bring
about greater and more prolonged elevations of adrenal corticosteroid
concentrations in blood.
Pain activates hypothalamic neurons producing vasopressin and stress-
induced analgesia has a component mediated by V1 vasopressin receptors.
The time-course and pathological impact of inflammatory conditions is
markedly influenced by vasopressin as well as cytokines produced by
vasopressinergic neurons of the hypothalamus.
The hormonal underpinning of the body’s reaction to stress, as first formulated by
Hans Selye in the 1930s (Selye, 1976), is a one of the most widely studied biological
responses. The present treatise will provide an overview of the role of the
nonapeptide vasopressin in this process. It will be highlighted that vasopressin is one
of three major hormones involved in the preservation of fluid and electrolyte balance
in the body the other two being aldosterone and angiotensin II. A readiness to pre-
empt body fluid loss is a good teleological fit with the stress-response, which is
geared to facilitate the restoration body homeostasis/allostasis in the face of virtually
any challenge that threatens to upset it (McEwen & Gianaros, 2011).
In order to keep the focus of a concise coverage, references to relevant reviews of
the subject will predominate to orient the reader, unless the information is considered
to be conceptually novel or unique to the subject matter and thus merit specific
VASOPRESSIN AND ITS DISTRIBUTION IN THE BRAIN AND THE PITUITARY
Vasopressin and its prohormone
Vasopressin was one of the first neuropeptides to be sequenced by Du Vigneaud
and colleagues (Ottenhausen, Bodhinayake, Banu, Stieg, & Schwartz, 2015). It is a
Figure 1 The primary structure of 8-Arg-Vasopressin and scheme of the propressorphysin
precursor. Sites of proteolytic processing occur between the boundaries of the boxes.
nonapeptide with an intrapeptide disulfide bond (Fig 1). The porcine pituitaries used
to purify the peptide yielded 8-Lys-vasopressin, but it later became clear that 8-Arg-
vasopressin (AVP) is the predominant variant in mammals including humans and
rodents. The carboxyl-terminal glycine of AVP is amidated. Later work shed light on
the structure of the propressorphysin precursor that is biosynthesized and
intracellularly processed to give rise to the biologically active hormone secreted by
magnocellular neurons of the hypothalamo-hypophyseal tract (Brownstein, Russell, &
Gainer, 1980). Currently, there is no reason to believe that central AVP producing
neurons projecting to various areas of the brain produce and secrete AVP differently
(Murphy, et al., 2012). The notion that an AVP-like peptide is produced in the
sympathetic nervous system (Hanley, et al., 1984) has not withstood the test of time.
However, a paracrine role for vasopressin locally produced in the adrenal medulla
seems likely (Guillon, et al., 1998).
Methods of identifying AVP producing neurons include immunocytochemical
localization of AVP, AVP-associated neurophysin (neurophysin II) or the carboxyl-
terminal glycopeptide of propressorphysin (copeptin) BOX 1 (Antoni, 1993).
involve the in situ
detection of AVP
these methods often
fail to identify nerve
terminals and thin
fibers with very low
amounts of peptide
and little if any
mRNA. The problem
may be overcome by
under the control of a
tissue specific AVP
promoter and map AVP projections with higher sensitivity as previously
accomplished for OXT neurons (Grinevich, Knobloch-Bollmann, Eliava, Busnelli, &
Chini, 2015). However, as yet, this approach has not been optimized to be
sufficiently specific for the detection of AVPergic nerve fibers throughout the brain
(Cui, Gerfen, & Young, 2013; Ueta, et al., 2005).
Localization of AVP in the brain
The sites of AVP production in the rat brain are nerve cell bodies in the hypothalamic
magnocellular paraventricular (PVN), supraoptic (SON) and accessory nuclei (AN),
the suprachiasmatic nucleus (SCN), the bed nucleus of the stria terminalis (BNST)
and the medial amygdaloid nucleus (MA) (de Vries & Miller, 1998; Sofroniew, 1980)
(Rood, et al., 2013). With respect to the neuroendocrine stress response the most
packaged! in! secretory! granules! in! a! manner! that! three!
into! the! systemic! circulation:! ! AVP,! neurophysin! II! and! the!
carboxyl-terminal! glycopeptide! (CCP1-39! (Seger! &! Burbach,!
1987)),! recently! renamed! as! copeptin! (Morgenthaler,! et! al.,!
2008).! ! It! is! of ! note! tha t
commonly!used!in!clinical!practice!because! of!the! biochemical!
features! of! the! peptide:! ! its! small! size,! low-abundance! and!
short! half-life! make! testing! for! AVP! labor-intensiv e.! The! high !
level! binding! of! AVP! to! platelets! adds! further! complications!
(Morgenthaler,! et! al.,!20 08).!By! contrast,!copeptin! (Fig!1)! the!
carboxyl-terminal! glycoprotein! fragment! of! the!
propressorphysin! precursor! that! is! co-released! with! AVP,
relatively! stable! in! the! posterior! pituitary! (Seger! &! Burbach,!
1987)!as! well! as! blood! plasma! and! is! increasingly! used! as! an!
significant pathways are the hypothalamo-hypophyseal and hypothalamo-
infundibular tracts (Fig 2). Detailed descriptions of these pathways are widely
available (Antoni, 1986, 2007; Makara, Antoni, Stark, & Kárteszi, 1984; Swanson,
Sawchenko, Lind, & Rho, 1987; van Leeuwen, Verwer, Spence, Evans, & Burbach,
1998; Ziegler & Herman, 2002; Zimmerman, Nilaver, Hou-Yu, & Silverman, 1984).
Hypothalamo-hypophyseal tract (HHS)
In brief, axons originating from the hypothalamic magnocellular PVN, SON and AN
terminate in the posterior lobe of the pituitary gland (Fig 2), abutting on fenestrated
capillaries that carry the AVP secreted from the nerve endings to the systemic
circulation. The discovery of this system and its fundamental physiological role to
promote the reabsorption of water in the kidney is reflected by the designation of
AVP as antidiuretic hormone (Verney, 1946). It is of note here that magnocellular
axons coursing through the internal zone of median eminence towards the posterior
lobe also release AVP en passant, and this AVP finds its way into the pituitary portal
blood that irrigates the anterior pituitary gland (Antoni, 1993; Engelmann, Landgraf, &
Hypothalamo-infundibular tract (HIS)
Parvocellular neurons located in the medial aspect of the hypothalamic
paraventricular nucleus co-express AVP and 41-residue corticotropin releasing factor
(CRF41). The axons from these neurons take the same path towards the median
FIGURE 2 Schematic representation of the parvocellular hypothalamo-infundibular (blue)
and magnocellular hypothalamo-hypophyseal (yellow) vasopressin (AVP) producing
neuronal pathways of the brain. The left insert shows a detail of the median eminence where
axon terminals of parvocellular neurons (blue) co-release AVP (yellow) and 41-residue
corticotropin-releasing factor (CRF41, blue) into the pituitary portal circula tion.
Magnocellular axons in passage to the posterior lobe of the pituitary gland in the internal
zone release AVP (yellow) en passant into the pituitary portal circulation. The magnocellular
axon terminals in the neural lobe secrete AVP into the systemic circulation. The right insert
shows the arrangement of AVP producing cell bodies in the hypothalamic paraventricular
Legend: PVN - paraventricular nucleus, mp magnocellular part, pm - parvocellular part, SON –
supraoptic nucleus, OC – optic chiasm, 3V - third cerebral ventricle
eminence as the magnocellular AVP axons, but terminate in the external zone of the
median eminence abutting on fenestrated capillaries of the pituitary portal circulation.
The two peptides are co-packaged and co-released from the same secretory
granules (Antoni, 1986; Antoni, 1993; Swanson, et al., 1987) to regulate the cells of
the anterior pituitary gland (Fig 2) .
Other cell bodies and extrahypothalamic projections
Expression of AVP in the BNST is dependent on androgens hence males have a
higher level of expression than females. Neurons in the BNST and MA project
extensively to various sites in the brain (de Vries & Miller, 1998; Rood, et al., 2013).
Of particular note are the AVPergic pathways to the lateral septum, which are
thought to be relevant for social behaviour in rats (Caldwell, Lee, Macbeth, & Young,
2008). Another projection of apparent significance originates from the PVN to
innervate the ipsilateral CA2 area of the hippampus (Cui, et al., 2013). However, due
to the scarcity and difficulty of detecting vasopressin in centrally projecting axons, a
complete map of extrahypothalamic AVP pathways is yet to be compiled, but see
refs (Sofroniew, 1980) (Rood, et al., 2013) for catalogs using the classical methods.
It is of particular relevance in this respect to distinguish between the central
projections of hypothalamic AVP neurons and those in the BNST, MA and SCN and
their respective relevance, if any, to the stress response.
In summary the involvement of AVP neurons of the PVN, SON and the AN in the
stress response is well established. The contribution of the other AVP producing cell
groups remains to be investigated.
MOLECULAR AND CELLULAR PHYSIOLOGY OF VASOPRESSIN WITH
SPECIAL REFERENCE TO ANTERIOR PITUITARY CORTICOTROPE CELLS
Receptors and ligands
Once released, AVP may travel via the extracellular space or the blood stream to
engage one of the four types of cell surface receptors for neurohypophyseal
hormones. It has been reported that in the brain extracellular enzymatic activities
produce bioactive AVP metabolites [pGlu4, Cystine6]-AVP (4-9) and
[pGlu4,Cyt6]vasopressin-(4-8) (Reijmers, Baars, Burbach, Spruijt, & van Ree, 2001;
Reijmers, van Ree, Spruijt, Burbach, & De Wied, 1998). These peptides are
biologically active and according to one study, an activator of V1a receptors in the
hypothalamic supraoptic nucleus (Gouzenes, Dayanithi, & Moos, 1999). However,
the question of how these AVP-derived peptides are generated and whether or not in
quantities relevant for a pysiological role remains unanswered.
Properties of receptors for vasopressin
Receptors for the neurohypophyseal hormones vasopressin and oxytocin are in the
Class A superfamily of heptahelical receptor proteins (Gimpl & Fahrenholz, 2001),
previously referred to as G protein-coupled receptors. The neurohypophyseal
hormone receptors are produced from four different genes and are designated as
vasopressin-1a (V1a), -1b (V1b), -2 (V2) and oxytocin (OT) (Burbach, et al., 1995;
Gimpl & Fahrenholz, 2001; Koshimizu, et al., 2012), splice-variant isoforms have also
been reported (Vargas, et al., 2009). There is a long list of studies that have
contributed to the pharmacologic and functional characterization of these receptors
(Manning, et al., 2012), and it is important to acknowledge the outstanding work of
the laboratory of Maurice Manning in the field. Analogs produced and generously
distributed by this laboratory have been instrumental in the early pharmacologic
differentiation of neurohypophysial hormone receptors (Antoni, 1987) and have been
perfected over the years (Manning, et al., 2012). As yet, a high-resolution structural
map of a neurohypophysial hormone receptor is not available, but given the rapid
progress in this area it should not be far away.
Affinity-based analysis of the neurohypophyseal hormone receptors has indicated
that V1a, V1b and V2 receptors show marked preference (>100x) for AVP over OXT
(Manning, et al., 2012). In contrast, AVP is only 20-30 fold less potent than OXT on
recombinantly expressed OT receptors (Gimpl & Fahrenholz, 2001; Manning, et al.,
2012). The picture becomes more complicated when binding or bioactivity is studied
in preparations expressing native receptors. For instance, despite having low affinity
in displacing (Kd≈300 nM) 3H-AVP from rat pituitary or recombinant V1b receptors
(Manning, et al., 2012), OT stimulated the release of adrenocorticotropic hormone
(ACTH) at low nanomolar concentrations from rat anterior pituitary tissue (Antoni,
1987; Schlosser, Almeida, Patchev, Yassouridis, & Elands, 1994). Moreover, it has
been argued that this effect is mediated through V1b receptors (Schlosser, et al.,
1994). When OT is used as the tracer ligand in uterine, pituitary (Antoni, 1987) or
hippocampal membrane preparations (Barberis & Tribollet, 1996) AVP is equipotent
with OXT as a displacing ligand of 3H-OXT, which is in contrast to results with
recombinantly expressed human OT receptors (Manning, et al., 2012). Yet another
example is pain perception: OXT as well as AVP have been reported to be analgesic
when administered directly into the brain, the spinal cord, or systemically.
Surprisingly, genetic and pharmacologic manipulations both indicate that this effect is
mediated by V1a receptors (Schorscher-Petcu, et al., 2010). This kind of atypical
pharmacology may be due to hetero-dimerization between neurohypophyseal
receptors (Stoop, Hegoburu, & van den Burg, 2015) or even with other heptahelical
receptors such as CRF1 in corticotrope cells (Young, Griffante, & Aguilera, 2007).
However, as yet there is no convincing evidence that such heterodimers exist under
physiological conditions in vivo (Vischer, Castro, & Pin, 2015).
In summary, the current data indicate that physiological concentrations of AVP can
activate all four of the neurohypophyseal hormone receptors.
Tissue distribution of AVP receptors
The tissue distribution of the neurohypophyseal hormone receptors is moderately
informative: V1a, V1b as well as OT receptors are highly abundant in the brain
(Barberis & Tribollet, 1996) (Koshimizu, et al., 2012). Topographically, the
enrichment of V1b receptors in the CA2 area of the hippocampus is the most
remarkable feature (Caldwell, et al., 2008). This area of the brain is associated with
social recognition memory and AVP is known to have an important role in this
process (Stevenson & Caldwell, 2012). The V1a receptor is abundant in peripheral
tissues such as vascular smooth muscle and liver (Koshimizu, et al., 2012). The V1b
receptor mRNA is expressed at low levels in the lung and the pancreas (Koshimizu,
et al., 2012). From the point of view of neuroendocrine regulation it is of interest that
the expression of V1b receptors is enhanced by adrenal corticosteroids (Aguilera,
In contrast, to V1 receptors, V2 receptors are mainly expressed in the kidney and only
found at low abundance in the brain (Koshimizu, et al., 2012). OT receptors are
abundant in various areas of the brain reflecting the numerous CNS actions of OXT
– further physiologically relevant sites of expression are the mammary gland and the
uterus (Gimpl & Fahrenholz, 2001). The expression of OT receptors in the uterus
and the adenohypohysis is prominently controlled by estrogens (Gimpl & Fahrenholz,
Intracellular signaling pathways
Intercellular signals such as hormones and neurotransmitters are detected and
processed by target cells through biochemical reactions collectively known as
intracellular signalling mechanisms. Since the advent and the wide-scale application
of cDNA-cloning virtually any protein involved in intracellular signalling may be
analysed in a “cellular laboratory” i.e. heterologous expression system — designated
here as “in transfecto” (Gilman, 1995). As a result, the information available has
expanded exponentially and the major principle distilled after three decades of
studies is that the precise mode of operation of a given signalling protein is very
strongly dependent on its cellular context. Generalizations, such as “coupling of
receptor X to a member of the G protein subfamily Gi (G protein inhibitory to adenylyl
cyclase) entails that activation of X will inhibit the biosynthesis of cyclic AMP” are no
longer possible (Antoni, 2000). Instead, it is entirely conceivable that by activating the
same Gi-coupled receptor in a defined set of neurons, a neurotransmitter will inhibit
cAMP formation in the morning and enhance it the evening— the underlying
explanation is the rapid circadian change of the cellular context (Antoni, 2000).
In order to validate observations made “in transfecto” a logical step is to analyze
preparations derived from primary tissues in vitro. In the fields of cancer biology or
immune regulation such preparations are accessible with minimally invasive
technology even from human patients. Although more laborious, in vitro models
derived from animal and human tissues are widely used in neuroendocrine research.
However, it is amply clear that even short-term tissue-culture can markedly alter the
properties of cells (Nestor, et al., 2015), thus the applicability of the results to
physiological conditions may be questioned and require further targeted experimental
validation in vivo.
It seems well established that the effects of AVP in biological systems are mediated
by the four heptahelical receptors listed above. The mechanism of action of such
receptors is best understood by examining the intracellular signaling pathways that
are activated upon the binding of their ligand(s) (Hall, Premont, & Lefkowitz, 1999).
Importantly, these reactions are not restricted to primary interactions with G proteins.
Moreover, it is also clear that upon activation at the plasma membrane, some
heptahelical receptors are rapidly internalised within signalling bodies and continue
to generate a signal inside cells (Antoni, 2012; Jalink & Moolenaar, 2010).
Signaling reactions of V1 receptors
Activation of the V1 type receptors leads to stimulated phospholipase C through
coupling to Gq/11 proteins (Koshimizu, et al., 2012). The consequent increase in
inositol trisphosphate (IP3) triggers a rise in the concentration of intracellular free
Ca2+ from intracellular stores via IP3-receptor Ca2+-channels. In parallel
diacylglycerol, the other product of the phospholipase C reaction, enhances the
activity of protein kinase C alpha or beta (Koshimizu, et al., 2012).
The rise in intracellular Ca2+ and the activity of protein kinase C may affect a large
number of intracellular targets and thus the functional outcome of these signaling
events is preeminently dependent on the type of cell targeted by AVP. From the
point of view of the stress-response hypothalamic magnocellular AVP neurons,
parvocellular CRF41/AVP neurons and anterior pituitary corticotrope cells appear
most relevant. In the case of nerve cells Ca2+ signalling by AVP in the dendritic tree
can result in a primed state of excitability (Ludwig & Leng, 2006) without leading to
manifest changes in action potential firing patterns (Ludwig & Leng, 2006;
substrates of this effect
have not been
identified. In the case
of anterior pituitary
relatively high (>1 nM)
vasopressin can trigger
the release of ACTH.
When CRF41 is also
of ACTH release takes
place, and AVP is
effective at lower
is the potentiation of
cAMP signal by AVP
(Aguilera & Rabadan-
Diehl, 2000; Antoni,
1993) (Antoni, 2012).
The amplification of the
The! adrenocortical! response! to! stress! is! governed! by! a!
neuroendocrine! feedback! loop! (Fig! 3).! In! brief,! neural! and!
hormonal! afferent! input!act ivated! by! stress!co nverges!on! th e!
hypothalamus! to! evoke! the! release! of! CRF41! and! AVP! from!
hypothalamic! neurons! into!pituitary! portal! blood! and! thus!
stimulate! cells! of! the! adenohypophysis! to! release!
adrenocorticotropic! hormone! (ACTH)! into! the! systemic!
circulation.! ! ACTH! rapidly! stimulates! the! secretion! of! the!
adrenocortical! steroid! hormone! cortisol! (corticosterone! in!
rodents)! into! the! systemic! circulation.! In! turn,! adrenal!
corticosteroids! diminish! the! secretion! of! ACTH! by! exerting!
inhibitory! feedback! at! the! anterior! pituitary! gland,! in! the!
hypothalamus! and! further! sites! in! the! brain.! ! Inhibitory!
glucocorticoid! feedback! is! described! as! early! immediate!
(seconds! to! minutes),! early! delayed! (20-120! min)! and! late!
(>4h)! (Keller-Wood! &! Dallman,! 1984).! ! The! parvocellular!
CRF41/AVP!neurons! as!well! as! adenohypophysial!corticotrope!
cells! are! thought! to! be! direct! targets! of! all! three! types!
corticosteroid! inhibition! (Antoni,! 1993).! Importantly,! within!
sensitive! to! the! early! inhibitory! effects! of! glucocorticoids!
(Kovacs,! et! al.,! 2000;! Ma! &! Aguilera,! 1999).! In! contrast,! the!
secretion! and! expression! of! AVP! by! cells! of! the! HHS! are! not!
influenced! by! early!feedback!inhibition! ! (Kovacs,!et!al.,!2000),!
although! late! effects! may! become! apparent! (Greenwood,! et!
al.,! 2015).! ! The! organization! of! extrahypothalamic! neural!
cAMP signal by AVP beyond levels required for the full activation of ACTH secretion
(ca. 3 µM) also renders corticotrope cells resistant to the inhibitory action of adrenal
corticosteroids (BOX 2) (Antoni, 2012; Lim, Shipston, & Antoni, 2002).
Importantly, the effects of AVP to potentiate CRF41-induced ACTH release can be
largely mimicked by pharmacologic activation of protein kinase C. Plausibly, the
amplification of the CRF41-induced cAMP response by AVP in corticotrope cells is
attributable to an isoform of adenylyl cyclase (AC7) that is stimulated by protein
kinase C (Antoni, 2012). Leading on from this, the resistance to inhibition by
glucocorticoids is likely to be the consequence of the activation of depolarizing non-
selective cation conductances gated directly by high (>10µM) intracellular levels of
cAMP (Antoni, 2012). Similarly, V1a-receptor mediated neuronal depolarisation of
motoneurons in the facial nucleus has been attributed to the activation of non-
selective cation conductances directly gated by cAMP (Raggenbass, 2008; Wrobel,
Dupre, & Raggenbass, 2011).
The apparent G-protein independent coupling of V1a (Zhu, Tilley, Myers, Coleman, &
Feldman, 2013) as well as V1b (Kashiwazaki, et al., 2015; Koshimizu, et al., 2012)
receptors to ß-arrestin has been reported. In the case of the V1a receptor natively
expressed in myoblasts, the outcome of coupling to beta-arrestin was the activation
of extracellular signal regulated kinase 1 (ERK1) and protection from ischemic stress
(Zhu, et al., 2013). In another study cultured rat hippocampal neurons were protected
from the neurotoxic effects of glutamate and nutrient deprivation by AVP acting
through V1 receptors (Chen & Aguilera, 2010). In the case of the V1b receptor
recombinantly expressed in CHO cells, ß-arrestin driven internalization was much
greater upon exposure to AVP than for V1a receptors (Kashiwazaki, et al., 2015). This
raises the intriguing possibility that the V1b receptor is also geared to signal away
FIGURE 3 The neuroendocrine feedback loop of the hypothalamic-pituitary-
adrenocortical axis. Blue arrows indicate stimulation, red lines with bars inhibition. CRF
: 41-residue corticotropin-releasing factor, AVP : vasopre ssin, ACTH:
from the plasma membrane as recently reported for a number of heptahelical
receptors (Antoni, 2012; Jalink & Moolenaar, 2010).
Anecdotal reports of the coupling of V1a receptors to pertussis toxin sensitive G-
proteins have been published (Raggenbass, 2008) but not substantiated by
biochemical analysis (Raggenbass, 2008).
Signaling reactions of V2 receptors
The V2 receptor is well-known to stimulate adenylyl cyclase mediated synthesis of
cAMP by coupling to the Gs protein. It is also prominently linked to ß-arrestin
dependent signalling (Ren, et al., 2005). However, there is no significant evidence
linking V2 receptors to the stress response e.g. see (Balazsfi, et al., 2015).
FUNCTIONS OF VASOPRESSIN:
Body fluid homeostasis and connection to the stress response
Virtually all forms of stress require a state of cardiovascular readiness and thus
protection of blood volume and cardiac output. Activation of the sympathetic nervous
system by stress is a well-known mechanism geared to achieve this (Kvetnansky &
McCarty, 2007; Pacak & Palkovits, 2001). However, it is also clear that
osmoregulation of body fluids via vasopressin-like peptides is a phylogenetically
conserved phenomenon that is also prominent in mammals (Acher, 2002). A quick
catalogue of the effects of AVP on fluid handling reveals actions promoting fluid
conservation in the kidney, the lungs, the brain, the colon and the salivary glands
(Bridges, Rummel, & Wollenberg, 1984; Niermann, Amiry-Moghaddam, Holthoff,
Witte, & Ottersen, 2001; Pouzet, et al., 2001).
Neuroendocrinologists have argued for decades whether or not activation of the HHS
is an integral part of the stress-response (Antoni, 1993). It was broadly agreed that
the HHS is activated upon exposure to “physical” stressors such as ether,
immobilization, haemorrhage, strenuous exercise, pain as well as upon the
“metabolic” stress of severe insulin-induced hypoglycemia (Antoni, 1993). However,
an increase of AVP levels in the systemic circulation, indicative of an impact of HHS
activation outwith the brain has not been consistently demonstrated in these
paradigms, casting doubt over HHS involvement in the response to stress.
Suprisingly, in the last few years clinicians have begun to resolve this problem largely
due to the widespread availability of a simple and sensitive immunoassay for the
quantification of copeptin in blood plasma (Balanescu, et al., 2011; Morgenthaler,
Struck, Jochberger, & Dunser, 2008) (BOX 1).
The activation of the HHS AVP system above “normal” in patients with septic shock,
lower respiratory tract infection, myocardial infarction, stroke and metabolic
syndrome is beyond reasonable doubt (Enhorning, et al., 2011) (Katan & Christ-
Crain, 2010; Tasevska, Enhorning, Persson, Nilsson, & Melander, 2015). The crucial
question is what the role of HHS derived AVP might be in these conditions? With
respect to more classical stress paradigms, increases of plasma copeptin were
reported in small groups of healthy volunteers exposed to “emotional stressors”
(Urwyler, Schuetz, Sailer, & Christ-Crain, 2015). Moreover, significant correlation
between serum cortisol and copeptin levels were found in male but not female
volunteers subjected to social stress (Spanakis, Wand, Ji, & Golden, 2016). In sum,
whilst intriguing and potentially important, the copeptin data generated so far have
posed more questions about the pathophysiological role of HHS derived AVP than
they have answered (Enhorning, et al., 2011; Katan & Christ-Crain, 2010; Tasevska,
et al., 2015).
AVP and the hypothalamic-pituitary adrenocortical (HPA) axis
Over the years, the role of AVP in the HPA axis has been examined by a large
number of studies deploying various methods including AVP-neutralizing antibodies,
surgical/neurochemical lesions of AVP neurons and AVP antagonists (Antoni, 1993).
For the interpretation of such experiments it is important to bear in mind that current
evidence indicates that the neurophypohysial peptides AVP and OXT reduce the
activity of CRF41/AVP neurons of the HIS (Bulbul, et al., 2011; Plotsky, 1991;
Slattery & Neumann, 2008). Although the mechanism(s) underlying this effect
remains to be clarified, it implies that effective neutralization of the actions of AVP at
the hypothalamic level results in an enhancement of the hypothalamic drive to
stimulate adrenocortical steroid secretion. By contrast, the selective inhibition of
AVP at the pituitary level can effectively suppress HPA activation (Antoni, 1993).
Finally, any reduction of adrenocortical steroid output diminishes glucocorticoid
feedback inhibition and thus will tend to enhance the hypothalamo-hypophysial drive
during the course of an experiment. This kind of push-pull regulation will lead to a
new set-point of glucocorticoid feedback that will reflect the blockade of AVP actions
indirectly, through a series of complex interactions (Peters, et al., 2007). Overall,
the features listed above make the quantitative interpretation of these studies
difficult. Numerous papers and reviews of these approaches to the stress response
have been published (Antoni, 1993; Curley, et al., 2010; Engelmann, et al., 2004;
Goncharova, 2013; Griebel & Holsboer, 2012; Roper, O'Carroll, Young, & Lolait,
2011) providing accounts of the purported role(s) of AVP in different forms of stress.
In the following section a summary of the progress in the areas with high clinical
translational value and previously not reviewed with a focus on AVP will be covered.
The neuroendocrine feedback loop that governs the operation of the HPA axis is
outlined in BOX 2. An important feature of this system is that the parvocellular HIS
CRF41/AVP neurons are prominent targets of early delayed glucocorticoid feedback
inhibition whilst magnocellular AVP neurons of the HHS are not. Furthermore, within
the HIS, the expression of AVP is dynamically regulated by early delayed
glucocorticoid feedback inhibition (Ma & Aguilera, 1999) (Kovacs, Foldes, &
Sawchenko, 2000). In contrast, this does not appear to be the case in the HHS –
only late glucocorticoid inhibition has been demonstrated (Greenwood, et al., 2015).
However, the dramatic increase of AVP expression seen upon removal of adrenal
steroids in the HIS system does not take place in HHS AVP neurons (Antoni, 1986).
As the HHS AVP cells are equipped with the same type II glucocorticoid receptor as
the HIS CRF41/AVP cells (Kiss, Van Eekelen, Reul, Westphal, & De Kloet, 1988), it
is a long-standing conundrum as to exactly how this marked difference in the cellular
regulation of AVP gene-expression is achieved (Gainer, 2012; Greenwood, et al.,
2015)? The relative insensitivity of HHS AVP cells to glucocorticoid inhibition
together with independent measures of HHS AVP activation has led investigators to
conclude that forms of HPA activation that are resistant to inhibition by
glucocorticoids are dependent on the HHS AVP system (Antoni, 1993; Engelmann,
et al., 2004). A typical example is the stimulation of the HPA axis upon hemorrhage
The pituitary corticotrope cell is also an important site of glucocorticoid inhibition.
Variants of the dexamethasone suppression test, that are used as a diagnostic tool in
the clinical setting, essentially probe the efficacy of glucocorticoid feedback at the
anterior pituitary level (von Bardeleben & Holsboer, 1989) (Krishnan, et al., 1993). All
three phases of glucocorticoid feedback inhibition have been reported in corticotrope
cells. However, under physiological conditions early delayed inhibition appears most
relevant (Antoni, 1996). With respect to HPA activation that is resistant to
glucocorticoid inhibition it is worth recalling, that in pituitary corticotrope cells AVP
can induce “glucocorticoid escape” from early delayed feedback by switching CRF41
signalling to pathways that generate an exaggerated cAMP response and engage
new targets downstream of the cAMP signal (Antoni, 2012). Furthermore, it is
important to emphasize that glucocorticoid escape is apparent at concentrations of
AVP that are characteristic of magnocellular HHS AVP cells or chronically
hyperactive HIS CRF41/AVP cells.
In summary, the expression of AVP is tightly controlled by adrenal corticosteroids in
the parvocellular HIS system, but this is not the case for magnocellular AVP cells of
the HHS. Concordantly, glucocorticoid escape at the anterior pituitary level requires
AVP concentrations normally secreted by magnocellular AVP neurons.
Stress of pain and AVP
One of the classic stress paradigms is the pain induced by the injection of formalin
into the hind paw of rodents. The first evidence for the involvement of AVP in the
stimulation of ACTH release in vivo (Tilders, Berkenbosch, Vermes, Linton, & Smelik,
1985) was published with formalin stress. Importantly, synaptic activation of
magnocellular AVP neurons in the SON has been demonstrated upon electrical
stimulation of somatic afferents or application of noxious stimuli (Day & Sibbald,
1990; Hamamura, Shibuki, & Yagi, 1984; Kannan, Yamashita, Koizumi, & Brooks,
1988). Pain increases plasma AVP levels in man (Franceschini, et al., 1995;
Kendler, Weitzman, & Fisher, 1978). More recent work showed (Hitoshi Suzuki, et
al., 2009) that formalin stress as well as adjuvant-induced arthritis increase the
expression of AVP in the HIS as well as the HHS. However, the increase of HHS
AVP was more pronounced in adjuvant-induced arthritis in keeping with the signs of
diminished glucocorticoid suppression of the HPA axis (Silverman & Sternberg,
2012) in this condition.
A further aspect of AVP and pain is the finding that both AVP and OT are analgesic
when given systemically or intrathecally (Berkowitz & Sherman, 1982; Schorscher-
Petcu, et al., 2010). Is there a connection to stress-induced activation of AVP
neurons? A potentially important study reported a role for a V1a receptor haplotype in
the perception of pain by human volunteers (Mogil, et al., 2011). However, the
haplotype effect was only apparent in stressed males (Mogil, et al., 2011). Similar
findings were produced in mice. Exogenous administration of the weak V1 agonist
desmopressin produced analgesia in males with a low level of stress, but was
ineffective in subjects with higher levels of stress. The interpretation of these
findings is that endogenous AVP released during the stress response obliterated the
analgesic effect of desmopressin (Mogil, et al., 2011). The results represent a tour de
force of mouse and human genetics coupled to functional assays. Questions remain:
is it AVP or OXT that is the endogenous mediator (Schorscher-Petcu, et al., 2010)?
If AVP, is it derived from the AVP cells in the BNST and MA that are regulated by
testosterone? Which AVP neuronal pathways are involved (Millan, Schmauss,
Millan, & Herz, 1984; Rood, et al., 2013; Sofroniew, 1980), where is the site of
AVP and inflammation
Adrenal corticosteroids are potent endogenous immunomodulators (Mason, 1991;
Morand & Leech, 2001; Silverman & Sternberg, 2012). In rodents, the active
inflammatory phase of experimental autoimmune encephalomyelitis as well as
adjuvant-induced arthritis is characterised by extremely high levels of corticosteroids
in blood lasting several days (Mason, 1991) (Silverman & Sternberg, 2012). The
protracted increase of HPA activity is essential for the survival of the affected animals
(Mason, 1991). How are such high levels of corticosteroids, characteristic of severe
stress, maintained in the face of glucocorticoid feedback inhibition? Several lines of
evidence pointed towards the activation of the magnocellular HHS AVP system to
override glucocorticoid feedback inhibition (Antoni, 1993). More recently, this issue
was re-examined in rats expressing enhanced green fluorescent protein under the
control of the AVP promoter (Satoh, et al., 2015; Ueta, et al., 2005). The results
clearly showed a marked increase of AVP levels in the HSS as well as the HIS with
no sign of a similar enhancement of CRF41 expression (H. Suzuki, T. Onaka, et al.,
2009). Plasma levels of corticosterone and AVP were also increased in rats with
adjuvant-induced arthritis (H. Suzuki, T. Onaka, et al., 2009).
These results corroborate the notion that AVP-induced resistance to glucocorticoid
feedback is the key to the prolonged increase of the secretion of endogenous
adrenal steroids to combat autoimmune inflammation. By contrast, the same authors
reported that the acute HPA response to bacterially derived lipopolysaccharide
selectively activates the HIS CRF41/AVP cells (Suzuki, Kawasaki, Ohnishi,
Nakamura, & Ueta, 2009) indicating that the stimulation of HHS AVP expression is
induced by different neurohumoral afferentation as that produced by LPS. However,
under certain conditions, e.g. depletion of brain macrophages, administration of LPS
has been shown to induce c-fos expression in magnocellular neurons of the PVN
(Serrats, et al., 2010). Thus the effects of LPS on the HHS system appear
conditional. Indeed, interleukin-1b, a major mediator of the effects of LPS in the body,
excites AVP neurons in the SON via induction of the production of prostanoids – a
classic inflammation related pathway (Chakfe, Zhang, & Bourque, 2006). A further
notable finding is that HHS AVP neurons express and release interleukin-6 into the
systemic circulation in response to acute stress (Jankord, et al., 2010). Thus, HHS
AVP neurons contribute to the stress response by releasing bioactive products other
The picture that emerges from the analysis of HHS and HIS AVP neurons in
inflammation is that on the one hand, heightened activation of these cells allows
enhanced and prolonged secretion of adrenal corticosteroids by shifting the normal
feedback set-point of the HPA axis, thus producing “glucocorticoid escape”. On the
other hand, in response to stress HHS AVP cells release at least one potent pro-
inflammatory mediator into the blood stream the production of which is suppressed
by adrenal corticosteroids in cells of the immune system (A Munck, Guyre, &
Holbrook, 1984; A. Munck & Naray-Fejes-Toth, 1994). A key issue is whether or not
the increased levels of corticosteroids balance out the stress-induced pro-
inflammatory processes? If not, do stress-related maladaptational syndromes
invariably emerge upon long-term HHS AVP activation? Once more, as in the case of
the analgesic actions associated with stress, the genetic make-up of an individual will
likely have a major impact on the outcome of these two opposing processes (Mason,
1991; Silverman & Sternberg, 2012). We are entering the era of pharmacogenetics
and personalised medicine.
AVP and behavioural aspects of social stress
Generalised anxiety disorder, melancholic depression, post-traumatic stress disorder
and schizophrenia are relatively common mental illnesses that have been connected
to various forms of stress over the years (Fink, 2007). Swaab and co-workers
(Swaab, Bao, & Lucassen, 2005) concluded that in human post-mortem material
depression is characterised by the signs of prolonged activation of HIS CRF41/AVP
as well as HHS AVP neurons. These signs point to a shift in the set-point of the HPA
axis, which can be demonstrated in close to 40% of patients with depression
(Gillespie & Nemeroff, 2005). In addition to behavioural changes secondary to the
altered dynamics of the HPA axis, what alternative mechanisms may underlie the
alterations of behavior mediated by AVP during stress? A significant pointer is the
report by Cui and co-workers showing a direct neural pathway between the CA2
hippocampal region and the PVN (Cui, et al., 2013). The CA2 region is essential for
social memory (Hitti & Siegelbaum, 2014) and shows a marked enrichment of V1b
receptors when compared to neighboring brain regions (Caldwell, et al., 2008). More
recently, it was shown that viral expression of the V1b receptor in the CA2 region of
male mice with genetic deletion of the V1b receptor, restored socially motivated attack
behavior without altering anxiety-like behaviors (Pagani, et al., 2015). Facilitation of
aggressive behavior is a well-known facet of the stress-response (Kruk, Halasz,
Meelis, & Haller, 2004; Veenema & Neumann, 2007) and it is also conceivable that
these effects of AVP require adrenal corticosteroids (Kruk, et al., 2004). It also
remains to be clarified which subpopulation(s) of PVN AVP neurons gives rise to
axonal projections to the CA2 area?
The hormonal triad of aldosterone, angiotensin II and vasopressin has the mission to
preserve body fluids and salts, the fundamental requisites of the internal milieu of
vertebrates. The neuroendocrine stress response is palpably linked to fluid
preservation – ACTH also stimulates aldosterone, vasopressin is released into the
general circulation during physical stress and sympathetic activation increases the
formation of angiotensin II. From this rather simple teleologic principle, the plethora
of actions of AVP that are connected through stress is truly remarkable. Even more
intriguing is the fact that these actions can be traced back to the activity of a few
thousand neurons in the hypothalamus. There is still a lot to be learned about the
AVP component of stress: The role of epigenetic alterations in the dynamics of the
stress response (Murgatroyd & Spengler, 2011); the mapping in full of the anatomical
projections of stress responsive AVP neurons; the emerging role of AVP in the
metabolic syndrome (Enhorning, et al., 2011), the reasons behind the lack of efficacy
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