Next Article in Journal
Circulating Long and Circular Noncoding RNA as Non-Invasive Diagnostic Tools of Hepatocellular Carcinoma
Next Article in Special Issue
Pursuing Orally Bioavailable Hepcidin Analogues via Cyclic N-Methylated Mini-Hepcidins
Previous Article in Journal
Development of Three-Dimensional Human Intestinal Organoids as a Physiologically Relevant Model for Characterizing the Viral Replication Kinetics and Antiviral Susceptibility of Enteroviruses
Previous Article in Special Issue
Exploring the Use of Helicogenic Amino Acids for Optimising Single Chain Relaxin-3 Peptide Agonists
Article Menu

Article Menu

Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

The Biology of Vasopressin

by , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and *add Show full author list remove Hide full author list
Biology Department, Concordia University, Montreal, QC H4B 1R6, Canada
Author to whom correspondence should be addressed.
These authors contributed equally.
These authors contributed equally.
Biomedicines 2021, 9(1), 89;
Submission received: 8 December 2020 / Revised: 29 December 2020 / Accepted: 6 January 2021 / Published: 18 January 2021
(This article belongs to the Special Issue Peptide-Based Drug Development)


Vasopressins are evolutionarily conserved peptide hormones. Mammalian vasopressin functions systemically as an antidiuretic and regulator of blood and cardiac flow essential for adapting to terrestrial environments. Moreover, vasopressin acts centrally as a neurohormone involved in social and parental behavior and stress response. Vasopressin synthesis in several cell types, storage in intracellular vesicles, and release in response to physiological stimuli are highly regulated and mediated by three distinct G protein coupled receptors. Other receptors may bind or cross-bind vasopressin. Vasopressin is regulated spatially and temporally through transcriptional and post-transcriptional mechanisms, sex, tissue, and cell-specific receptor expression. Anomalies of vasopressin signaling have been observed in polycystic kidney disease, chronic heart failure, and neuropsychiatric conditions. Growing knowledge of the central biological roles of vasopressin has enabled pharmacological advances to treat these conditions by targeting defective systemic or central pathways utilizing specific agonists and antagonists.

Graphical Abstract

1. Introduction

Foreword: This review is the result of a didactic project at Concordia University in Montreal employing a novel “write to learn” pedagogy [1] that we have used successfully before [2,3]. Senior undergraduate students enrolled in a Comparative Physiology course for third-year Biology majors were taught experientially how to research and study the scientific literature to write a collaborative analytical review on the biological activity of vasopressin. We apologize to those colleagues whose important research could not be cited because of space or pedagogic constraints.
In humans and rodents, arginine vasopressin (AVP) regulates several diverse physiological functions: Fluid balance, blood osmolarity, reproduction, complex behavior, memory, and learning. An antidiuretic hormone, vasopressin is a nonapeptide conserved from invertebrates to vertebrates that displays species-specific amino acid (aa) changes in positions 3 and 8 [4]. Vasopressin is thought to have enabled the survival of land-dwelling organisms by regulating tubular reabsorption in the kidneys to maintain internal water homeostasis and blood osmolarity [5]. Here, we review the biology of AVP through examination of its normal physiological roles in the kidneys and heart, its neurological and behavioral effects, how AVP dysfunction contributes to pathologies such as polycystic kidney disease (PKD), heart failure (HF), neuropsychiatric disorders, and the pharmacological manipulation of AVP-dependent pathways.

1.1. Early Discoveries

The antidiuretic function of AVP was first demonstrated in 1913 by F. Farini in Venice and, independently, by von den Velden in Düsseldorf, who injected extracts from the posterior lobe of the pituitary gland into anesthetized men to control excessive water loss due to diabetes insipidus (a rare condition unrelated to type 1 diabetes (reviewed in [6]) or pituitary damage [7,8,9]. At the time, bovine pituitary extract was known for its oxytocic (triggers uterine contractions) and pressor (raises blood pressure) properties, albeit the underlying mechanisms were unknown. In 1927, two active components were isolated and called respectively α- and β-hypophamines (i.e., amines driven from the hypophysis). Their chemical synthesis shortly followed, and the resultant products were assigned the trade names oxytocin (OT; α-hypophamine or Pitocin) and AVP (β-hypophamine or Pitressin) [10,11]. AVP receptors (R) Avpr1a (today’s V1aR), Avpr2 (V2R), and Avpr1b (V1bR) were subsequently cloned, as well as the single oxytocin receptor Oxtr (OTR) [12,13,14,15,16,17,18,19].

1.2. AVP Function

AVP secretion from the posterior pituitary is triggered by changes in the electrolyte-water balance affecting intravascular blood volume and osmolality, that respectively activate baroreceptors [20] and osmoreceptors [21]. When serum sodium (Na+) levels rise above 145 mmol/L, the resulting hypernatremia activates the hypothalamic osmoreceptors within the organum vasculosum lamina terminalis (OVLT) and the subfornical organ that signal to the supraoptic (SON) and paraventricular nuclei (PVN) and induce AVP secretion by the posterior pituitary into the bloodstream [5,22]. Changes in osmolality of the thalamic magnocellular cells activate nonselective cation channels, increase the action potentials firing rate, and trigger AVP release from axon terminals ([23], reviewed in [24]). Heightened hematic AVP leads to water reabsorption by the kidneys to dilute Na+ in the organism [20,21,23]. Conversely, decreased osmolality promotes AVP retention and increased water excretion [25]. AVP interacts with the transmembrane receptors V1aR, V1bR, and V2R expressed by several cell types [25,26,27]. Patients suffering from congestive heart failure (CHF) display high basal levels of AVP, which increases vascular smooth muscle tone [28,29,30]. Changes in blood volume, especially when paired to a drop in blood pressure, e.g., caused by hemorrhage, activate baroceptors, and can also induce AVP secretion [5]. In the brain, AVP functions as a neuropeptide regulating social behavior [31,32,33,34].

1.3. AVP Gene Expression

The AVP gene expression is tightly controlled. The AVP promoter contains a cyclic AMP (cAMP) response element (CRE) recognized by the phosphorylated CRE-binding protein in response to increased intracellular cAMP [35,36,37]. The AP1 and AP2 transcription factors promote AVP transcription, while the glucocorticoid receptor represses it [38]. Furthermore, the AVP mRNA is regulated post-transcriptionally through polyadenylation. In the hypothalamic cells of salt-deprived rats, the AVP mRNA poly(A) tail length was longer than in non-salt-deprived rats [39,40]. Long polyA tails are likely to increase translation of the cognate protein [41]. In mammalian neurons, the poly(A) binding protein bound to the AVP mRNA on the “dendritic localization sequence” increased mRNA stability and translation [39].

1.4. AVP Synthesis

AVP is produced from a 164 aa long pre-pro-hormone precursor in the body of the magnocellular neurons of both PVN and supra-ventricular nucleus of the hypothalamus [42], and at lower levels in parvocellular neurons of the PVN [43]. Pre-pro-AVP contains an N-terminal signal peptide, followed by the AVP nonapeptide, and the open reading frames of regulatory peptides neurophysin-2 and copeptin [44]. Figure 1A illustrates the pre-pro-AVP processing and post-translational modification [38,45].
Pro-AVP is stored in membrane-associated granules and released in response to increased extracellular fluid osmolarity and osmoreceptor activation [25]. The threshold of AVP release and plasmatic AVP levels differ in men and women and among individuals [46,47]. Mature AVP is the cyclic nonapeptide Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 (reviewed in [42]) in which the two cysteines form a disulfide bridge, and the terminal carboxyl residue is modified post-translationally into a primary amide ([37,48], Figure 1B). AVP circulates as a free hormone and is degraded enzymatically in the liver and kidney within 10–30 min of release [49].

1.5. AVP Receptors

V1aR, V1bR, and V2R are G protein-coupled receptors (GPCRs) that interact with trimeric G proteins, Gq/11 and Gs [50]. Each receptor has distinct tissue expression. The BGee gene expression database [51] lists 168 human tissues expressing V1aR mRNA, 59 for V1bR, and 129 for V2R and species-specific relative variability. V1aR expression in the Suprachiasmatic nucleus (SCN) exhibits diurnal rhythmicity [52]. Functional information for organs and tissues relevant to this review is listed in Table 1.

1.5.1. Kidney

The V1aR receptor is expressed by the vesicular and smooth muscle cells of the renal vessels and mediates the AVP vasopressor effects [67,83]. V1aR is also expressed in the collecting duct. Upon AVP binding, the Gq protein subunits dissociate and the αq subunit activates phospholipase C-β (PLCβ), which increases diacyl-glycerol (DAG) and inositol triphosphate (IP3), releases calcium (Ca2+) from the endoplasmic reticulum and activates the transient receptor potential (TRP) ion channel, which replenishes the Ca2+ stores from extra-cellular Ca2+ [84]. V2R is expressed in the nephron, the basolateral membrane of epithelial cells of the distal convoluted tubule, and the collecting duct where it mediates the AVP antidiuretic action [24,85,86]. In the collecting duct, AVP binding to V2R dissociates the receptor from the Gs protein subunits (Figure 2), which activates a signal transduction cascade producing cAMP and Ca2+ release from ryanodine-sensitive stores [87]. Such a cascade leads to protein kinase A (PKA)-dependent phosphorylation of aquaporin 2 (AQP2) [88]. AQP2 is a water channel stored in intracellular vesicles [89]. Upon AVP signaling, AQP2 vesicles are shuttled to and fused with the apical membrane, which enhances water reabsorption (Figure 2) [90,91]. AVP can be translocated to the cytoplasm and degraded by the proteasome, which dampens signaling and results in water excretion as diluted urine [92,93,94].

1.5.2. Heart

Myocytes of the cardiac vascular smooth muscle express V1aR [83,96]. While AVP can protect the heart from myocardial injuries [97,98], high levels of circulating AVP and V1aR overexpression have been associated with heart failure, indicating the importance of V1aR signaling strength [83].

1.5.3. Brain

In the brain, V1aR, V1bR, and V2R mediate adaptive behavioral responses to centrally released AVP. Typically, the brain displays species-specific AVP receptor expression patterns, with V1aR and V1bR most commonly found in the lateral cortex [67,68]. The corticotropic cells of the human anterior pituitary are rich in V1bR, which promotes adrenocorticotropic hormone (ACTH) production. ACTH stimulates the adrenal synthesis of cortisol, androgens, and aldosterone ([63,64], reviewed in [24]). Under stress, V1bR contributes to activate the hypothalamo-pituitary-adrenal axis [99]. Implicating AVP in social behavior and development, V1bR is also found in the CA2 region of the hippocampus and the anterior region of the amygdala [100]. RT-PCR analysis indicated stable V2R mRNA expression in the rat cerebrum and age-dependent decline in the hippocampus [55]. However, V2R function in the brain is unclear [31].

1.5.4. Other Tissues

In the human and rodent pancreas, AVP binding to V1bR augments insulin release [72,101]. Conversely, AVP engagement of hepatic V1aR increases glycemia and, when prolonged, may predispose to glucose intolerance and diabetes [102,103]. As detected by RT-PCR, the V1bR mRNA is also expressed in the adrenals and small intestine, albeit how these cells respond to AVP remains undefined [72].

1.5.5. Regulation of AVP Receptor Expression

Several tissue-specific signals affect AVP receptor expression transcriptionally and post-transcriptionally. In the collecting duct, metabolic acidosis increases V1aR [104] and decreases V2R expression [85]. Dehydration upregulates V2R expression [85]. V2R engagement by AVP stimulates faster ubiquitin-dependent degradation than steady-state turnover [105]. V2R expression levels are sex-dependent, which may have a bearing for AVP-V2R-linked pathologies (e.g., PKD below) [106]. In addition, both V1bR transcription and translation change in response to stress [107,108].

1.5.6. Receptor Desensitization

Alike other GPCRs, the signaling cascade from AVP receptor activation also results in receptor desensitization, which interrupts downstream signaling [109,110,111]. This occurs through GPCR phosphorylation by GPCR kinases, arrestin binding, G protein uncoupling, and receptor internalization. V1aR is rapidly recycled to the cell surface; in contrast, V2R is sequestered in perinuclear recycling compartments [112,113,114]. Because AVP receptors can be phosphorylated by several kinases, heterologous desensitization can occur in response to different signals (e.g., angiotensin II) [115].

2. AVP-Related Renal Pathology

Because of its many physiological roles, AVP dysregulation due to both loss-of-function and gain-of-function leads to widespread complications. Mutations in the AVP, V2, and AQP2 genes cause forms of diabetes insipidus that have been extensively reviewed elsewhere [6,116,117,118]. Here, we will focus on AVP gain-of-function in PKD.

2.1. Polycystic Kidney Disease and AVP

In PKD, cystic degeneration of the kidneys progressively affects their function, disrupting water balance. Autosomal dominant PKD (ADPKD) is a hereditary renal disease affecting 12.5 million people worldwide [119]. The majority of mutations found in ADPKD patients map to the PKD1 and PKD2 genes [119,120]. In rare autosomal-recessive PKD (ARPKD), mutations disrupt the PKHD1 gene [119,121,122]. PKD1, PKD2, and PKHD1 all encode transmembrane proteins, namely polycystin 1, polycystin 2, and fibrocystin [122]. Polycystin 1 is considered an orphan, atypical GPCR. Polycystin 2 is a Ca2+ permeable non-selective cation channel with homology to the TRP superfamily [123,124,125]. Fibrocystin, or polyductin, is also a transmembrane protein [126,127,128,129]. Polycystin 1, polycystin 2, and fibrocystin interact and can be found at the cilium, considered critical for PKD [124,125]. The precise mechanisms of cyst formation and growth are unknown; however, several changes are known to occur at the molecular, cellular, and physiological levels that affect tubular homeostasis and function. Neoplastic-like cystic growth and tubular epithelial cell apoptosis characterize PKD [119,130]. Early PKD stages are characterized by abnormally high fluid excretion, which causes dehydration and activates compensatory AVP release to stem water loss [119,130,131,132,133,134]. While in ADPKD congenital cysts only occur in 1–3% of nephrons, continued cystic growth and new cysts eventually deform and compress the surrounding parenchyma, impair nearby nephrons, and increase cell death. At advanced PKD stages, kidneys can quadruple their volume and reach the size of a football [119]. These events eventually overwhelm renal compensation, causing end-stage renal disease and kidney failure in half of the ADPKD patients [119,130]. AVP, V2R, and cAMP signaling are all altered in PKD [122,135,136,137,138]. Moreover, AVP loss of function in the PCK rat (AVP−/−) increases renal cAMP and ERK phosphorylation, reminiscent of ARPKD [122].
PKD1 and PKD2 mutations reduce Ca2+ signaling in the primary cilia and endoplasmic reticulum (ER) of the epithelial cells of the renal tubule, which in turn increases intracellular cAMP and fluid excretion ([133], Figure 3). Concomitant up-regulation of V2R expression in PKD kidneys further elevates intracellular cAMP, which in turn increases protein kinase A activity and Cl- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR), fueling cystic cellular proliferation and Cl--dependent fluid secretion [131,139]. Finally, in PKD, V2R may redistribute apically in the tubular cells [137]. ARPKD cells also feature AVP/V2R upregulation, cAMP-activated cellular proliferation, and reduced intracellular Ca2+ [135,140,141]. Therapeutic targeting of the AVP system with V2R antagonists appears to be moderately effective in the short term and is discussed in Section 5.1.2.

2.2. Biological Sex and PKD

Like female mice, women display higher V2R mRNA expression than their male counterparts ([106], reviewed in [142]) corroborating evidence for sex-specific phenotypic, clinical, and/or pharmacological differences in the AVP response. The relationship between sex and PKD appears complicated and is incompletely understood. Notably, while men seem more sensitive than women to several kidney diseases, in ADPKD such difference appeared to be reduced, implicating that women may instead have faster disease progression [143]. More than 80% of ADPKD and severe polycystic liver disease patients are females, suggesting that hormonal regulation may contribute to disease severity [119]. However, in a recent study, female patients displayed slower cystic progression than males, adding to a recent proposal that men may be more severely compromised by ADPKD than women, despite the latter being more affected numerically [144]. In contrast, both sexes are equally affected by ARPKD [119]. Future studies will be needed to clarify this important aspect of the PKD pathophysiology.

3. AVP and Heart Failure

As of the year 2015, cardiovascular disease had caused the death of 17.3 million people worldwide, to which HF has been one of the leading causes [145]. The decline in the heart’s ability to effectively operate as a fluid pump and maintain proper systemic circulation, HF translates clinically into decreased cardiac output and stroke volume, regardless of total circulatory blood volume [146]. Chronic HF patients exhibit two to three times higher serum concentrations of AVP (2.5–6.4 pM) compared to healthy individuals (<1.6 pM). Higher AVP levels are associated with later stages of HF and suggest that AVP may contribute to disease progression [147,148]. AVP synthesis within the SON and the PVN is coordinated with the afferent signaling pathways from baroreceptors localized within the aorta, the carotids, the cardiac atria, and left ventricle [149,150]. In HF, decreased circulating blood volume reduces baropressor sensitivity and stimulates non-osmotic AVP release [146]. Moreover, as a vasoconstrictor, AVP raises blood flow. Specific to HF, systemic AVP release augments peripheral vascular resistance and compensates for reduced cardiac output and stroke volume in the short-term [149,151]. However, chronic AVP hyperstimulation eventually impairs the heart’s mechanical function, promotes extensive cardiac remodeling, and causes fluid imbalances that synergistically exacerbate cardiac dysfunction and lead to HF [147,152].

3.1. AVP-V1aR Signaling and Cardiac Contractility

In HF patients, elevated plasmatic AVP appears to correlate with V1aR mRNA upregulation in the left ventricular myocardium [98]. Similarly, HF induced by left coronary ligation in the Ntac:SD+/+ rat also featured upregulated V1aR mRNA within the left ventricle [153]. Probing of the AVP-V1aR signal transduction pathway revealed that overexpression of the human V1aR in mice cardiac myocytes, (V1atTa/+) augmented AVP-V1aR signaling and promoted Gαq protein recruitment to the plasma membrane, increased D-myo-inositol 1,4,5 trisphosphate signaling and Ca2+ mobilization (Figure 4A). V1aR overexpression leads to extensive myocardial contraction, hypertrophy, vasoconstriction, and reduced cardiac contractility [154,155]. Persistent AVP-V1aR signaling also disrupts β-adrenergic receptor activation and signaling (Figure 4B) [156]. Hence, physiological coupling of higher AVP secretion and V1aR density appears to underlie changes in cardiac contractility and morphology in HF.

3.2. AVP-V1aR Signaling and Cardiac Remodeling

Cardiac fibroblasts are non-contractile cells amounting to up to 60% of the heart, essential to maintain the structural integrity of the heart’s extracellular matrix (ECM) [152]. Activation of V1aR signaling was found to promote cardiac fibroblast proliferation and function [147,152]. In cardiac fibroblasts, AVP-V1aR dependent signaling recruits GRK2 and β-arrestin1/2 and increases expression of matrix metalloproteinases MMP2 and MMP9, functioning in ECM degradation and tissue remodeling [147,157]. Moreover, AVP-V1aR signaling induces phosphorylation of mitogen-activated ERK1/2 kinase that binds GRK2 and β-arrestin1/2 and stimulates cardiac fibroblasts proliferation [151,157]. Extensive ECM deposition follows increased expression of connective tissue growth factor and endothelin-1 that respectively promote collagen synthesis and inhibit MMP1 [147]. The combined vasopressor function of AVP and endothelin-1 increase peripheral vascular resistance and cardiac afterload, which—when prolonged—lead to adaptive myocardial hypertrophy to try maintaining cardiac output to the periphery [146,149].

3.3. AVP-V2R Signaling for Fluid Volume Retention and Cardiac Function

In a healthy individual, the baroreceptor-mediated non-osmotic release of AVP is meant to limit perturbation from normonatremic and euvolemic states and ensure proper cardiac compliance. However, in the case of progressive HF, sustained non-osmotic AVP release will induce AQP2-mediated water reabsorption at renal collecting ducts and cause dilutional hyponatremia (serum Na+ level <134mEq/L) and expansion of the circulatory blood volume [158,159]. A coronary-ligated rat model of congestive HF indicated that AQP2 was also upregulated and further impaired cardiac performance through greater infarction of the left ventricular free wall [160,161]. Moreover, prolonged AQP2 translocation to the apical membrane increased systemic fluid retention and fluid saturation/hypervolemic state and cardiac preload. If sustained, this condition stresses the diastolic wall, and promotes MMP activation and cardiac hypertrophy [147]. Altogether, chronic AVP secretion coupled with activation of V1aR and V2R signaling contribute to a vicious cycle of extensive myocardial remodeling and inefficient contractile events that usually escalate into fatal HF [160,162].

4. AVP and Brain Function

AVP functions as a neurohormone regulating memory and attention [163,164], increases neural transmission in the amygdala [165,166] and participates in the neuroendocrine stress response [167]. AVP modulates social behavior in several fish, amphibian, vertebrate, and mammalian species with sexual dimorphic displays ([168,169,170], reviewed in [31]).
The AVP-synthesizing magnocellular neurons of the PVN project to the posterior pituitary and release AVP into the circulatory system to induce water retention [171,172,173,174]. In contrast, the parvocellular neurons project from the PVN to the median hypothalamic eminence, and release AVP to trigger the secretion of ACTH and several anterior pituitary hormones [172,175]. Other AVP-synthesizing neurons can be found in the medial amygdala, the bed nucleus of the stria terminalis (BNST), and the SCN, which all project centrally to the brain preoptic and olfactory areas, hypothalamic, and extra-hypothalamic regions [54,176,177,178]. These neurons are thought to be the source of neural AVP because the blood brain barrier is impermeable to plasmatic AVP [166,179,180,181]. Seven of the nine amino acids in AVP are identical to OT, another neurohormone, due to the partial overlap of their genes [182,183]. The distinct expression and distribution of AVP, OT, their receptors, and the reach of their neuronal projections further intertwine these systems (reviewed in [68,166]). AVP and OT can function variably and antagonistically, depending on sex and several context-dependent factors. While AVP appears anxiogenic, OT is anxiolytic and pro-social [33,181,184,185,186,187]. Recently, it was found that the similarity between OT and AVP results in their binding to each other’s receptors and substantial crosstalk in vivo, especially at high AVP and OT concentrations [27]. Integrative functional models of AVP and OT signaling are needed to reconcile observations made in disparate experimental set ups and behavioral paradigms, with primary focus on OT and male individuals, to refine understanding of the neural circuitry regulating social behaviors. Here, we will examine the AVP functions, referring readers interested in the biology of OT to comprehensive reviews [163,166].

4.1. AVP and Animal Behavior

AVP and its non-arginine vasopressin relatives (VP) preside to sociality in several rodents (rats, mice, hamsters, voles, jerboas) as well as birds and fish through largely conserved neural networks in the amygdala, BNST, lateral septum, medial preoptic area, anterior hypothalamus, and the periaqueductal grey [68,169,188,189,190,191,192,193,194,195,196]. Despite these similarities, the behavioral responses appear both species-specific and may vary among conspecifics, likely due to the differential distribution and expression of neural AVP receptors and influence by gonadal hormones [169,177,196]. Note, V1aR and V1bR are widely expressed in the brain (Table 1). To probe the AVP neural functions in vivo, gene knock-out of AVP or its receptors and pharmacological targeting of AVP receptors have been employed in combination with behavioral tests such as the forced swim test, which assesses the animal’s overwhelm from a prolonged drowning threat and the elevated plus maze test that measures anxiety ([43], reviewed in [197]). In such contexts, the AVP response appeared largely subject-specific and influenced by social experience, hormonal status, and the neuronal connections within the hypothalamus and between the hypothalamus and other areas [178,198,199].

4.1.1. V1bR and Behavior

V1bR engagement by AVP in the anterior pituitary and adrenal medulla promotes the release of key stress hormone ACTH [25,200,201]. This adds to the V1aR-mediated synthesis and cortisol release occurring in the adrenals [70]. Denoting altered stress response, during the forced swim test and elevated plus maze, male V1bR−/− mice displayed reduced resting levels and impaired ACTH release compared to controls [25,99]. V1bR may also mediate aggression [202,203], and the V1bR−/− mice display social deficits [204,205].

4.1.2. V1aR and Behavior

V1aR may regulate individual recognition, pair-bonding, sexual behavior, social memory, and aspects of parental care (e.g., maternal aggressive behavior, anxiety, depression) [25,169,206,207,208,209]. Intracerebral AVP microinjection and V1aR overexpression in the lateral septum both improved social recognition; conversely, both V1aR knockout and administration of V1aR antagonists severely impaired sociality [208,210,211,212].

4.1.3. Recognition

In rodents, species-specific recognition is largely based on olfactory cues, and depends on species-specific distribution of AVP-immunoreactive nerve fiber types [213]. Pharmacological or genetic V1aR targeting prevented short-term social recognition in rats, possibly through changes in olfactory processing [178,214,215].

4.1.4. Aggression

Several AVP-immunoreactive neurons in the medial amygdala and BNST that project to the lateral septum and AVP-immunoreactive projections to the anterior hypothalamus were implicated in aggression in rodents [169,216,217,218,219]. While this theme is conserved in several species, anatomical specializations are thought to underlie species-specific behaviors. For example, VP infusion into the septum inhibited aggression against intruders in the field sparrow, a territorial species [217], whereas it increased aggression in the colonial zebra finch [218]. Note, the septum is involved in social cognition, stress response, and anxiety.

4.1.5. Parental Care

In rodents, parental care (e.g., pup licking and grooming) is necessary for both early development and the adoption of similar nurturing behavior as adults. Genetic and pharmacologic evidence indicated that in both sexes, pup grooming and maternal post-partum aggression are mediated by the AVP/VP network and the neuronal connections between the hippocampus and both the amygdala and the basal forebrain (reviewed in [81]). Engaging in parental behavior increased expression of both AVP and its receptors, which consolidates gene expression and behavior [209,220,221,222,223].

4.1.6. Sexual Behaviors

The effects of AVP/VP on sexual behavior have been thoroughly reviewed elsewhere [224].

4.1.7. Differential Sex Response to AVP

In most species (except hyenas and rats), estrogen and androgens seem to increase AVP levels [177]. In rats, testosterone was found to modulate AVP/VP receptor expression and localization, as well as the number of AVP-immunoreactive neurons [225,226,227,228]. Conversely, castration reduced AVP expression in a subpopulation of cell bodies within the BNST of amphibians, birds, and mammals [148,229]. Note, the BNST is a sexually dimorphic center that integrates limbic information and valence monitoring and has been implicated in several psychiatric disorders. Corroborating the importance of AVP signaling strength, compared to females, male rats showed denser AVP-immunoreactive fibers in the lateral septum and lateral habenular [230,231,232] that may impact a subset of AVP/VP responses ([233], reviewed in [31]). In naked mole rats, breeding dominant males and females were found to contain more AVP-immunoreactive neurons than subordinates [177,234]. In mandarin voles, dominant and subordinate females displayed different distributions of AVP-immunoreactive neurons in the PVN and SON [235].

4.1.8. Changes in AVP-Signaling

The AVP system appears to adaptively respond to conditions and environments. For example, maternal stress during late pregnancy reduced V1aR neural expression and impaired pup sociality [236]. Seasonal breeding [237,238] and fatherhood [239,240,241,242] also appear to modulate AVP signaling.

4.1.9. Circadian Response

V1aR signaling affects circadian rhythmicity [71,243]. In mice, circadian non-endocrine regulation elicited by SCN neurons triggered AVP release, OVLT activation, and increased thirst before sleep to counter dehydration during the night hours [244,245].

4.2. AVP and Human Behaviour

The AVP (and OT) systems underlie human social cognition, with short-term effects on context-specific behavioral responses and long-term behavioral regulation (e.g., anxiety, reward) [246,247,248]. Alike other species, OT is pro-social [148,249,250,251,252]. Depending on context, AVP can promote either pair bonding and cooperation or threat reaction and anxiety [253,254,255]. Patients with certain personality disorders presented high AVP in the cerebrospinal fluid, and often systemically [174,256]. Autism spectrum disorder (ASD), Williams syndrome, schizophrenia, depression, social anxiety, and attachment disorders all respond to AVP receptor blockade or seem linked to AVP and OT [166,257,258,259,260,261,262,263,264,265,266,267,268]. Reduced AVP was found in patients with schizophrenia and bipolar disease, with lower AVP levels possibly predisposing to psychoses, independent of OT [264,269]. Social stress is known to increase odds to develop psychiatric disorders [270], albeit its effects on AVP are unknown. Suggesting that AVP signaling may interface with the limbic system, serotonin modulates AVP release and V1aR activation [271,272]. Certain polymorphic variants of V1aR and the serotonin transporter SLC6A4 that are linked to creative and behavioral traits have been found frequently associated in dancers and may relate to capacity for social empathy [273]. Depression, impulsivity, and violence seem causally linked to AVP regardless of other factors, e.g., sex, stressors [274,275,276,277]. Childhood stress appears to affect sociality through AVP [278]. Underscoring the complexity of the AVP neural network, the AVP system was found to respond to both gonadal steroids and genetic background (more below), and life history influences the individual responses to specific contexts [67]. Possibly contributing to physiological and individual diversity, sensitivity to OT signaling and its AVP-balancing functions seem to be established during early life [279]. Moreover, the AVP-responsive amygdala, cingulate gyrus, and hypothalamus all impinge on social behavior [261,280,281,282]. Recently, AVP-immunoreactive projections have been found in the human male agranular insula [282], a region of the brain neocortex presiding to sensory processing, high-level cognition, and affection [283]. Thus, AVP appears to be central to the human neural developmental pathways. Polymorphic microsatellites upstream of the V1aR gene may influence expression levels in the amygdala [284,285,286,287,288]. Furthermore, some V1aR gene polymorphisms associate with behavioral traits, including novelty seeking, sexual behaviors, musicality, and dance ([261,273,289,290], reviewed in [166]). Specific polymorphisms and simple sequence repeats in the V1aR gene associate with schizophrenia and ASD, social cognition deficits [34,291], and behaviors including aggression, altruism, depression, and empathy [269,292,293]. Polymorphisms reducing AVP gene expression have been linked to schizophrenia [294]. Consistent with a causal relationship, AVP administration lessened the negative symptoms of some schizophrenic patients [264].
To study the effects of AVP in human subjects, intra-nasal administration is used in combination with functional MRI (fMRI) to reveal the brain areas with changes in deoxyhemoglobin concentration in response to AVP [33,178,295,296]. As in animals, intranasal AVP administration may increase endocrine stress by augmenting amygdala activity [165] and promoting ACTH secretion [167] and favor negative responses in ambiguous social situations [297]. While AVP reduced friendliness in men, it increased it in women [298]. Brain fMRI during a Prisoner’s Dilemma Game revealed that, upon intranasal administration of 20 international units (IU) of AVP and compared to placebo, AVP increased BNST activity and reciprocated cooperation in men [255,299]. Note, the AVP and OT-responsive BNST interfaces with the brain areas regulating affiliation, parental care, sexual behaviors, communication, and aggression [190,300]. In contrast, in women, AVP activated the left caudate nucleus and left amygdala and increased cooperation following partner defection [299]. In men, perceived unreciprocated cooperation appeared to reduce the activation of the right amygdala, which is responsible for processing negative emotions, and the anterior insula [148]. Interestingly, these patterns may be influenced by personality traits. Upon AVP administration, male participants with high neuroticism score also displayed higher activity in the anterior cingulate cortex, medial prefrontal cortex, and lateral temporal lobe in response to unreciprocated cooperation [301]. Note, such regions mediate emotion, decision-making, and language. Conversely, cooperation activated the right insula, which is linked to body awareness [301]. AVP increased male cooperation in risky yet rewarding choices through decreased activity of the left dorsolateral prefrontal cortex (which modulates cognitive flexibility during risky cooperation) [254]. AVP may also alter male emotional processing. Normally, seeing facial displays of fear or anger changes activity in the subgenual cingulate of the medial prefrontal cortex, which is part of the limbic system. However, men treated with 40 IU) of intranasal AVP neither recognized the difference between such displays, nor showed differential brain activity, and exhibited decreased functional connectivity between the subgenual and supragenual cingulate [262]. Thus, the human AVP response seemingly shares traits with other mammals and birds, and also displays unique species- and individual-specific traits due to individual genetics, life history, and situation, which all contribute to the integration of sensory processing and behavior to adapt to specific contexts.

5. Pharmacological Modulation of the AVP Pathways

The human AVP pathway has been targeted pharmacologically using AVP receptor agonists and antagonists. Agonists are mainly AVP analogs that bind to the same receptor site (orthosteric) as natural AVP, which are used to bolster AVP signaling in loss-of-function conditions, e.g., diabetes insipidus and septic shock ([302], reviewed in [303]). Conversely, antagonists lessen elevated AVP signaling (gain-of-function) in HF, PKD, and secondary shock, and are aquaretic, i.e., promote excretion of solute-free water (reviewed in [304]).

5.1. Vasopressin Receptor Antagonists

Known also as vaptans, nonpeptide AVP receptor antagonists are administered orally or intravenously to bind specifically and competitively to renal and cardiac V2R [305,306]. Tolvaptan, lixivaptan, satavaptan, and mozavaptan each have distinct chemical features that uniquely influence receptor affinity and biological activity (Table 2). Upon receptor interaction, the vaptans prevent AQP2 translocation to the apical membrane of the renal collecting duct and increase aquaresis [307,308,309]. Conivaptan exhibits high affinity for both V1aR and V2R. Upon binding to localized V1aRs, conivaptan can limit myocardial hypertrophy [310,311]. Balovaptan selectively binds to neural V1aRs and exhibits potential for treating human behavioral disorders [312,313]. Relcovaptan similarly binds to V1aRs and is used to induce local vasodilatation in Raynaud’s disease and reduce preterm labor contractions [314,315]. Note, Raynaud’s disease causes vasoconstriction in hands and feet, and may lead to localized tissue necrosis. Nelivaptan interacts with neuronal V1bRs, reduces ACTH secretion by approximately 15%, and is a potential anxiolytic and antidepressant [64,316,317]. Nelivaptan may also function in other tissue contexts. Treatment of rodent and human pancreatic β-cell isolates eliminated insulin release [101]. Moreover, V1bR-selective non-peptide antagonist SSR-149415 abolished Ca2+ release, glucagon secretion, and cell proliferation of a glucagon-secreting α-pancreatic cell line [72]. Non-competitive AVP receptor antagonists may affect downstream receptor signaling independent of AVP binding and may offer functional selectivity, i.e., modulation of only a subset of a receptor’s downstream signaling pathways. Preserving some of the wanted responses induced by binding of the natural ligand, such molecules may reduce the side effects caused by receptor blockade. While this is an untapped potential in vasopressin research, one such compound, the VRQ397 peptide, appeared specific for V2R, behaved as an allosteric modulator, and exhibited aquaretic properties [318].

5.1.1. V2R Antagonism in Heart Disease Therapy

Because of their aquaretic effects, the vaptans are used in patients with congestive HF with simultaneous hypervolemic hyponatremia and edema [305,341]. The inhibitory effect of vaptans on the V2R signaling cascade prevents the translocation of AQP2 channels to the apical membrane of the renal collecting duct cells. The ensuing aquaresis corrects existing fluid and/or electrolytic imbalances [158]. Administration of 30–45 mg of tolvaptan can reduce edema, body weight, and serum sodium level without compromising blood pressure and renal function [306].

5.1.2. V2R Antagonism in PKD Therapy

Based on the strong AVP deregulation observed in ADPKD and ARPKD animal models, strategic reduction of AVP-mediated signaling and intracellular cAMP using V2R antagonists was found to reduce both cystic fluid secretion and cyst size in murine PKD models [122,342,343] and PKD patients [130,136,321]. The V2R antagonist and benzazepine derivative OPC31260 [338] reduced cystic volume and inhibited new cyst formation in several rodent PKD models [122,342] and nephronophthisis, another renal cystic disease [344]. With its high affinity for V2R, OPC31260 can displace AVP from V2R and V1aR (IC50, respectively 1.4 × 10−8 M and 1.2 × 10−6 M) [338]. In the ADPKD model of the Pkd−/tm1Som mice, OPC31260 lowered renal cAMP, AQP2, and V2R expression (all higher than normal in ADPKD) and reduced kidney weight to wild-type levels [342]. OPC31260 also improved the PCK AVP−/− ARPKD rat, reducing both cAMP and kidney-specific ERK phosphorylation, and overall improving water reabsorption, reducing kidney cysts and weight compared to vehicle-treated controls [122]. Due to these early encouraging results, tolvaptan, which was already approved to treat heart disease in several countries, was entered in clinical trials to normalize V2R signaling in PKD.

5.1.3. Clinical Trials

Tolvaptan inhibited cystic cell proliferation by reducing activation of the B-Raf/MEK/ERK pathway and Cl secretion [136]. Several clinical trials are listed in the clinical trials databases for tolvaptan, other vaptans, and AVP agonists (,, Supplementary Table S1). The phase 3 TEMPO trial included 1445 patients between the ages of 18 and 50, who had a kidney volume of at least 750 mL (i.e., 50% increase compared to healthy subjects) and a creatinine clearance of at least 60 mL/min (i.e., moderately declined renal function) [321]. During a three-year period, tolvaptan treatment almost halved kidney growth and slowed kidney functional deterioration by a slope of −2.61 (mg/mL)−1 per year, compared with −3.81 (mg/mL)−1 from placebo [321,345]. These exciting results were tempered by adverse effects observed in the tolvaptan group as opposed to placebo. Despite adoption of split-dose protocols that reduce nightly excretion, uncomfortable aquaresis challenged patient compliance. Importantly, troubling unrelated hepatotoxicity raised concerns for the safety of long-term use [321,345,346]. A recent one-year trial, REPRISE, involved 1370 patients aged 18 to 55 with a GFR of 25 to 65 mL/min/1.73 m2, and patients aged 56 to 65 with an associated GFR of 25 to 44 mL/min/1.73 m2 (i.e., patients with CKD stage G3 and impaired kidney function) [130]. In this follow-up trial, tolvaptan similarly retarded the loss of renal function for advanced PKD patients, but elevated hepatic enzymes (e.g., alanine aminotransferase) to the same levels observed in chronic hepatitis, although levels renormalized upon treatment termination [130]. Tolvaptan is recommended to patients with the following characteristics: 1—age 18–50 years old, 2—fast disease progression, 3—low water and/or high salt intake [347]. Tolvaptan effectiveness may attenuate over time [321]. Importantly, none of the V2R antagonists affected liver cysts (frequent in ADPKD patients) because hepatocytes do not express V2R [348]. Currently, tolvaptan represents the only approved therapy available to (a subset of) ADPKD patients. Further studies are ongoing (Supplementary Table S1) and required to clarify its effects and applicability, as well as explore the properties of other prospective V2R antagonists that could potentially benefit a wider group of ADPKD patients.
Balovaptan was used in Improve Social Communication in Autism (VANILLA), a phase 2 clinical trial of 223 individuals with ASD. Doses of 4mg and 10mg of balovaptan improved the score of the Vineland-II Adaptive Behavior Scale of ASD patients with few adverse side effects [312]. Thus, balovaptan may be a prospective alternative to antipsychotics, that were instead found to increase risk of obesity, type 2 diabetes, and cardiovascular disease [349].

5.2. Synthetic AVP Analogs

Several AVP synthetic analogs (Table 3) are used in therapy or are undergoing clinical trials for conditions with reduced AVP signaling (Supplementary Table S1).

6. Conclusions

Conserved among the terrestrial vertebrates, vasopressins are a group of nonapeptide hormones central to maintain homeostasis and adapt to environmental and social changes in shared, species-specific, and individual ways. Characterized by an arginine in position 8, the human AVP has been studied for its effects on the kidney, heart, and brain physiology. Several cell types produce AVP and release it in the blood stream to affect water re-adsorption in the terminal region of the renal tubule, and vasoconstriction to conserve water and facilitate the cardiovascular function. AVP also functions as an endocrine modulator that affects leukocytes and immunity and the insulin/glucagon pathways. Because of the blood brain barrier impermeability, AVP is released centrally in the brain. The distribution and localization patterns of AVP-immunoreactive cells display sex- and individual specificity. New AVP-immunoreactive structures are expected to be revealed by neuroimaging advances. Widespread and regulated expression of three main high-affinity AVP receptors, V1aR, V1bR, V2, and at least one other receptor, OTR, that can be cross-activated at high AVP concentrations, indicates that many cell types can respond to AVP signaling, depending on context, which is consequential for pharmacological intervention.
While the fluid homeostasis and pressor functions of AVP are believed to have enabled colonization of a terrestrial environment, neural AVP appears to be equally important for survival in that it coordinates sensory processing and behavioral modulation through the intricate connections of AVP-immunoreactive neurons in distinct brain areas. Some AVP-dependent pathways are sensitive to gonadal steroids, serotonin, OT, and possibly other hormones, which enables adaptive fine-tuning of the AVP-dependent physiology to the changing needs of a growing individual (e.g., sexual behavior, reproduction, seasonal adaptations), and sociality (e.g., individual recognition, emotional processing, social stress, communication, parental behavior).
Altered AVP signaling has been linked to diabetes insipidus, PKD, HF, and psychiatric conditions including ASD, bipolar, and borderline personality disorder. Thus, modulators of AVP physiology have pharmacological interest. Receptor antagonists with distinct selectivity, affinity, and half-life in vivo have been identified and are being used to modulate branches of the AVP physiological responses in cardiac and renal disease, as well as to relieve neurological symptoms and ameliorate the social difficulties in borderline personality disorder. Deciphering the mechanistic aspects of AVP signaling both in tissue- and cell-specific detail, their crosstalk and systemic integration is therefore fundamental to understand how AVP adaptively integrates physiology and behavior and develop safe and effective therapeutics to treat AVP-related conditions including PKD, HF, and ASD.

Supplementary Materials

The following are available online at, Table S1: Clinical trials.

Author Contributions

The following authors contributed text on the topics as indicated: N.A., C.M.A., B.B., M.B. (Marion Bardies) on AVP in animal parental care; G.B., R.B., L.B., M.B. (Minky Benedikt), Z.C. on the heart-brain axis; T.D., J.D. (Jocelyn Dault), J.C., A.C., I.D. on AVP and metabolic disorders; E.D., J.D. (Jonathan Dias), N.F., S.E.-K., A.F. (Anika Forget) on chronic kidney disease; T.I.; E.G.; E.H., P.H., C.H. on AQP2 and CHF; A.G., A.F. (Alexa Fox), M.C.G., M.G., O.G., S.R. (Saad Razzaq), R.S., S.R. (Samantha Rhainds), D.S., D.R., on AVP and water homeostasis; C.K., T.K., S.K., E.K., H.K.K. AVP-related diseases; D.M.R., D.L., T.B.U.L., F.M., Y.F.L. on AVP and kidney permeability; S.M., K.M., A.N., K.N.-D., J.O. on AVP and circadian rhythms; C.O.-L., E.P., H.W.P., L.S.P., K.P.-C. on AVP in heart disease; J.P.M., C.-A.P., S.P., M.P., R.R. on AVP, brain and behaviour. L.T., N.S.M., K.S., S.S.F., M.S. on AVP, CHF and treatments; A.J.W., A.W., C.W., M.W.T., S.T.-C., S.T.-H. on OT roles in ASD; S.S. wrote text on AVP synthesis and processing, pharmacology, generated the graphical abstract and Figure 1, and edited the manuscript; C.M.-B. wrote the section on AVP and PKD, contributed to the pharmacology section, made Figure 2, Figure 3 and Figure 4, and curated and edited the manuscript; J.O. wrote the section on heart disease, contributed to the pharmacology section, designed Figure 4, and edited the manuscript; K.M., T.K., and P.H. respectively contributed to the sections on AVP and brain function, pharmacology and to manuscript editing; C.G. planned the review contents, directed the assignment and editing activities, co-wrote the section on AVP neurobiology, and edited the manuscript. All authors have read and agreed to the published version of the manuscript.


This research received no external funding. As an educational project, this manuscript was curated on a volunteer basis from each and all authors, including the corresponding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.


We are grateful to Concordia University Biology Librarian Katharine Hall for support and expert assistance throughout this project; Almira Kurbegovich for critical comments to the manuscript; William D. Lubell for the vasopressin structure. C.G. is a member of the Center of Excellence in Research on Orphan Diseases—Fondation Courtois.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Gamberi, C.; Hall, K. Undergraduates can publish too! A case study of a scientific team writing assignment leading to publication. Int. J. Sci. Educ. 2019, 41, 48–63. [Google Scholar]
  2. Selber-Hnatiw, S.; Rukundo, B.; Ahmadi, M.; Akoubi, H.; Al-Bizri, H.; Aliu, A.F.; Ambeaghen, T.U.; Avetisyan, L.; Bahar, I.; Baird, A.; et al. Human gut microbiota: Toward an ecology of disease. Front. Microbiol. 2017, 8, 1265. [Google Scholar] [CrossRef]
  3. Selber-Hnatiw, S.; Sultana, T.; Tse, W.; Abdollahi, N.; Abdullah, S.; Al Rahbani, J.; Alazar, D.; Alrumhein, N.J.; Aprikian, S.; Arshad, R.; et al. Metabolic networks of the human gut microbiota. Microbiology 2020, 166, 96–119. [Google Scholar] [CrossRef]
  4. Hoyle, C.H. Neuropeptide families and their receptors: Evolutionary perspectives. Brain Res. 1999, 848, 1–25. [Google Scholar] [CrossRef]
  5. Boone, M.; Deen, P.M. Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption. Pflugers Arch. 2008, 456, 1005–1024. [Google Scholar] [CrossRef] [Green Version]
  6. Fujiwara, T.M.; Bichet, D.G. Molecular biology of hereditary diabetes insipidus. J. Am. Soc. Nephrol. 2005, 16, 2836–2846. [Google Scholar] [CrossRef]
  7. Farini, F. Diabete insipido ed opoterapia. Gazz. Osped. Clin. 1913, 34, 1135–1139. [Google Scholar]
  8. Qureshi, S.; Galiveeti, S.; Bichet, D.G.; Roth, J. Diabetes insipidus: Celebrating a century of vasopressin therapy. Endocrinology 2014, 155, 4605–4621. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Vongraven, D. Die nierenwirkung von hypophysenextrakten meschen. Berl. Klin. Wochenscgr. 1913, 50, 2083–2086. [Google Scholar]
  10. du Vigneaud, V.; Gish, D.T.; Katsoyannis, P.G. A synthetic preparation possessing biological properties associated with arginine-vasopressin. J. Am. Chem. Soc. 1954, 76, 4751–4752. [Google Scholar] [CrossRef]
  11. du Vigneaud, V.; Ressler, C.; Swan, J.M.; Roberts, C.W.; Katsoyannis, P.G. The synthesis of oxytocin. J. Am. Chem. Soc. 1954, 76, 3115–3121. [Google Scholar] [CrossRef]
  12. Birnbaumer, M.; Seibold, A.; Gilbert, S.; Ishido, M.; Barberis, C.; Antaramian, A.; Brabet, P.; Rosenthal, W. Molecular cloning of the receptor for human antidiuretic hormone. Nature 1992, 357, 333–335. [Google Scholar] [CrossRef] [PubMed]
  13. Kimura, T.; Tanizawa, O.; Mori, K.; Brownstein, M.J.; Okayama, H. Structure and expression of a human oxytocin receptor. Nature 1992, 356, 526–529. [Google Scholar] [CrossRef] [PubMed]
  14. Lolait, S.J.; O’Carroll, A.M.; McBride, O.W.; Konig, M.; Morel, A.; Brownstein, M.J. Cloning and characterization of a vasopressin V2 receptor and possible link to nephrogenic diabetes insipidus. Nature 1992, 357, 336–339. [Google Scholar] [CrossRef] [PubMed]
  15. Morel, A.; O’Carroll, A.M.; Brownstein, M.J.; Lolait, S.J. Molecular cloning and expression of a rat V1a arginine vasopressin receptor. Nature 1992, 356, 523–526. [Google Scholar] [CrossRef]
  16. De Keyzer, Y.; Auzan, C.; Lenne, F.; Beldjord, C.; Thibonnier, M.; Bertagna, X.; Clauser, E. Cloning and characterization of the human V3 pituitary vasopressin receptor. FEBS Lett. 1994, 356, 215–220. [Google Scholar] [CrossRef] [Green Version]
  17. Sugimoto, T.; Saito, M.; Mochizuki, S.; Watanabe, Y.; Hashimoto, S.; Kawashima, H. Molecular cloning and functional expression of a cDNA encoding the human V1b vasopressin receptor. J. Biol. Chem. 1994, 269, 27088–27092. [Google Scholar] [CrossRef]
  18. Thibonnier, M.; Auzan, C.; Madhun, Z.; Wilkins, P.; Berti-Mattera, L.; Clauser, E. Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor. J. Biol. Chem. 1994, 269, 3304–3310. [Google Scholar] [CrossRef]
  19. Rozen, F.; Russo, C.; Banville, D.; Zingg, H.H. Structure, characterization, and expression of the rat oxytocin receptor gene. Proc. Natl. Acad. Sci. USA 1995, 92, 200–204. [Google Scholar] [CrossRef] [Green Version]
  20. Mckinley, M.; Mathai, M.; McAllen, R.; McClear, R.; Miselis, R.; Pennington, G.L.; Vivas, L.; Wade, J.D.; Oldfield, B.J. Vasopressin secretion: Osmotic and hormonal regulation by the lamina terminalis. J. Neuroendocrinol. 2004, 16, 340–347. [Google Scholar] [CrossRef]
  21. Bourque, C.W.; Oliet, S.R.; Richard, D. Osmoreceptors, osmoreception, and osmoregulation. Front. Neuroendocrinol. 1994, 15, 231–274. [Google Scholar] [CrossRef] [PubMed]
  22. Kim, S.W. Hypernatemia: Successful treatment. Electrolyte Blood Press. 2006, 4, 66–71. [Google Scholar] [CrossRef] [PubMed]
  23. Bichet, D.G. Central vasopressin: Dendritic and axonal secretion and renal actions. Clin. Kidney J. 2014, 7, 242–247. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Van Gastel, M.D.A.; Torres, V.E. Polycystic kidney disease and the vasopressin pathway. Ann. Nutr. Metab. 2017, 70, 43–50. [Google Scholar] [CrossRef]
  25. Koshimizu, T.A.; Nakamura, K.; Egashira, N.; Hiroyama, M.; Nonoguchi, H.; Tanoue, A. Vasopressin V1a and V1b receptors: From molecules to physiological systems. Physiol. Rev. 2012, 92, 1813–1864. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Cuzzo, B.; Padala, S.A.; Lappin, S.L. Vasopressin (antidiuretic hormone, ADH). In StatPearls [Internet]; StatPearls Publishing: Treasure Island, FL, USA, 2020. [Google Scholar]
  27. Song, Z.; Albers, H.E. Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery. Front. Neuroendocrinol. 2018, 51, 14–24. [Google Scholar] [CrossRef]
  28. Francis, G.S.; Goldsmith, S.R.; Levine, B.; Olivari, M.T.; Cohn, J.N. The neurohumoral axis in congestive heart failure. Ann. Intern. Med. 1984, 101, 370–377. [Google Scholar] [CrossRef] [PubMed]
  29. Goldsmith, S.R.; Francis, G.S.; Cowley, A.W., Jr.; Levine, T.B.; Cohn, J.N. Increased plasma arginine vasopressin levels in patients with con-gestive heart failure. J. Am. Coll. Cardiol. 1983, 1, 1385–1390. [Google Scholar] [CrossRef] [Green Version]
  30. Riegger, G.A.J.; Liebeau, G.; Kochsiek, K. Antidiuretic hormone in congestive heart failure. Am. J. Med. 1982, 72, 49–52. [Google Scholar] [CrossRef]
  31. Dumais, K.M.; Veenema, A.H. Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior. Front. Neuroendocrinol. 2016, 40, 1–23. [Google Scholar] [CrossRef] [Green Version]
  32. Goodson, J.L.; Thompson, R.R. Nonapeptide mechanisms of social cognition, behavior and species-specific social systems. Curr. Opin. Neurobiol. 2010, 20, 784–794. [Google Scholar] [CrossRef] [PubMed]
  33. Heinrichs, M.; von Dawans, B.; Domes, G. Oxytocin, vasopressin, and human social behavior. Front. Neuroendocrinol. 2009, 30, 548–557. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Zink, C.F.; Kempf, L.; Hakimi, S.; Rainey, C.A.; Stein, J.L.; Meyer-Lindenberg, A. Vasopressin modulates social recognition-related activity in the left temporoparietal junction in humans. Transl. Psychiatry 2011, 1, e3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Iwasaki, Y.; Oiso, Y.; Saito, H.; Majzoub, J.A. Positive and negative regulation of the rat vasopressin gene promoter. Endocrinology 1997, 138, 5266–5274. [Google Scholar] [CrossRef]
  36. Kuwahara, S.; Arima, H.; Banno, R.; Sato, I.; Kondo, N.; Oiso, Y. Regulation of vasopressin gene expression by cAMP and glucocorticoids in parvocellular neurons of the paraventricular nucleus in rat hypothalamic organotypic cultures. J. Neurosci. 2003, 23, 10231–10237. [Google Scholar] [CrossRef] [Green Version]
  37. Yoshida, M. Gene regulation system of vasopressin and corticotropin-releasing hormone. Gene Regul. Syst. Bio. 2008, 2, 71–88. [Google Scholar]
  38. Ball, S.G. The neurohypophysis: Endocrinology of vasopressin and oxytocin. In Endotext [internet]; Feingold, K.R., Anawalt, B., Boyce, A., Chrousos, G., de Herder, W.W., Dungan, K., Grossman, A., Hershman, J.M., Hofland, J., Kaltsas, G., et al., Eds.;, Inc.: South Dartmouth, MA, USA, 2017; p. 2017. [Google Scholar]
  39. Mohr, E.; Kachele, I.; Mullin, C.; Richter, D. Rat vasopressin mRNA: A model system to characterize cis-acting elements and trans-acting factors in dendritic mRNA sorting. Prog. Brain Res. 2001, 139, 211–224. [Google Scholar]
  40. Zingg, H.H.; Lefebre, D.L.; Almazan, G. Regulation of poly(A) tail size of vasopressin mRNA. J. Biol. Chem. 1988, 15, 11041–11043. [Google Scholar] [CrossRef]
  41. Preiss, T.; Brakier-Gingras, L.; Lapointe, J. The end in sight: Poly(A), translation and mRNA stability in eukaryotes. In Madame Curie Bioscience Database [Internet]; Landes Bioscience: Austin, TX, USA, 2000; pp. 2000–2013. [Google Scholar]
  42. Rotondo, F.; Butz, H.; Syro, L.V.; Yousef, G.M.; Di leva, A.; Restrepo, L.M.; Quintanar-Stephano, A.; Berczi, I.; Kovacs, K. Arginine vasopressin (AVP): A review of its historical perspectives, current research and multifunctional role in the hypothalamo-hypophysial system. Pituitary 2016, 19, 345–355. [Google Scholar] [CrossRef]
  43. Morales-Medina, J.C.; Witchey, S.K.; Caldwell, H.K. The role of vasopressin in anxiety and depression. In Melatonin, Neuroprotective Agents and Antidepressant Therapy; López-Muñoz, F., Srinivasan, V., de Berardis, D., Álamo, C., Kato, T.A., Eds.; Springer: New Delhi, India, 2016; pp. 667–685. [Google Scholar]
  44. Waller, S.J.; Ratty, A.; Burbach, J.P.H.; Murphy, D. Transgenic and transcriptional studies on neurosecretory cell gene expression. Cell. Mol. Neurobiol. 1998, 18, 149–171. [Google Scholar] [CrossRef]
  45. Acher, R.; Chauvet, J.; Rouille, Y. Dynamic processing of neuropeptides. J. Mol. Neurosci. 2002, 18, 223–228. [Google Scholar] [CrossRef]
  46. Perucca, J.; Bouby, N.; Valeix, P.; Bankir, L. Sex difference in urine concentration across differing ages, sodium intake, and level of kidney disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007, 292, R700–R705. [Google Scholar] [CrossRef] [PubMed]
  47. Roussel, R.; Fezeu, L.; Marre, M.; Velho, G.; Fumeron, F.; Jungers, P.; Lantieri, O.; Balkau, B.; Bouby, N.; Bankir, L.; et al. Comparison between copeptin and vasopressin in a population from the community and in people with chronic kidney disease. J. Clin. Endocrinol. Metab. 2014, 99, 4656–4663. [Google Scholar] [CrossRef] [PubMed]
  48. Barberis, C.; Mouillac, B.; Durroux, T. Structural bases of vasopressin/oxytocin receptor function. J. Endocrinol. 1998, 156, 223–229. [Google Scholar] [CrossRef] [Green Version]
  49. Baumann, G.; Dingman, J.F. Distribution, blood transport, and degradation of antidiuretic hormone in man. J. Clin. Investig. 1976, 57, 1109–1116. [Google Scholar] [CrossRef]
  50. Hoffert, J.D.; Pisitkun, T.; Saeed, F.; Song, J.H.; Chou, C.L.; Knepper, M.A. Dynamics of the G protein-coupled vasopressin V2 receptor signaling network revealed by quantitative phosphoproteomics. Mol. Cell. Proteomics 2012, 11, M111.014613. [Google Scholar] [CrossRef] [Green Version]
  51. Bastian, F.B.; Roux, J.; Niknejad, A.; Comte, A.; Costa, S.S.F.; de Farias, T.M.; Moretti, S.; Parmentier, G.; de Laval, V.R.; Rosikiewicz, M.; et al. The Bgee suite: Integrated curated expression atlas and comparative transcriptomics in animals. Nucl. Acids Res. 2020, gkaa793. [Google Scholar] [CrossRef]
  52. Young, W.S., III; Kovacs, K.; Lolait, S.J. The diurnal rhythm in vasopressin V1a receptor expression in the suprachiasmatic nucleus is not dependent on vasopressin. Endocrinology 1993, 133, 585–590. [Google Scholar] [CrossRef]
  53. Greenberg, A.; Verbalis, J.G. Vasopressin receptor antagonists. Kidney Int. 2006, 69, 2124–2130. [Google Scholar] [CrossRef] [Green Version]
  54. Holmes, C.L.; Patel, B.M.; Russell, J.A.; Walley, K.R. Physiology of vasopressin relevant to management of septic shock. Chest 2001, 120, 989–1002. [Google Scholar] [CrossRef] [Green Version]
  55. Kato, Y.; Igarashi, N.; Hirasawa, A.; Tsujimoto, G.; Kobayashi, M. Distribution and developmental changes in vasopressin V2 receptor mRNA in rat brain. Differentiation 1995, 59, 163–169. [Google Scholar] [CrossRef] [PubMed]
  56. Mutig, K.; Paliege, A.; Kahl, T.; Jons, T.; Muller-Esterl, W.; Bachmann, S. Vasopressin V2 receptor expression along rat, mouse, and human renal epithelia with focus on TAL. Am. J. Physiol. Renal Physiol. 2007, 293, F1166–F1177. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Carmosino, M.; Brooks, H.L.; Cai, Q.; Davis, L.S.; Opalenik, S.; Hao, C.; Breyer, M.D. Axial heterogeneity of vasopressin-receptor subtypes along the human and mouse collecting duct. Am. J. Physiol. Renal Physiol. 2007, 292, F351–F360. [Google Scholar] [CrossRef] [PubMed]
  58. Hirashawa, A.; Shibata, K.; Kotosai, K.; Tsujimoto, G. Cloning, functional expression and tissue distribution of human cDNA for the vascular-type vasopressin receptor. Biochem. Biophys. Res. Commun. 1994, 203, 72–79. [Google Scholar] [CrossRef] [PubMed]
  59. Park, F.; Mattson, D.L.; Skelton, M.M.; Cowley, A.W., Jr. Localization of the vasopressin V1a and V2 receptors within the renal cortical and medullary circulation. Am. J. Physiol. 1997, 273, R243–R251. [Google Scholar] [CrossRef]
  60. Saito, M.; Tahara, A.; Sugimoto, T.; Abe, K.; Furuichi, K. Evidence that atypical vasopressin V2 receptor in inner medulla of kidney is V1b receptor. Eur. J. Pharmacol. 2000, 401, 289–296. [Google Scholar] [CrossRef]
  61. Gozdz, A.; Szczepanska-Sadowska, E.; Szczepanska, K.; Maslinski, W.; Luszczyk, B. Vasopressin V1a, V1b and V2 receptors mRNA in the kidney and heart of the renin transgenic TGR(mRen2)27 and Sprague Dawley rats. J. Physiol. Pharmacol. 2002, 53, 349–357. [Google Scholar]
  62. Cottet-Maire, F.; Avdonin, P.V.; Roulet, E.; Buetler, T.M.; Mermod, N.; Ruegg, U.T. Upregulation of vasopressin V1a receptor mRNA and protein in vascular smooth muscle cells following cyclosporin A treatment. Br. J. Pharmacol. 2001, 132, 909–917. [Google Scholar] [CrossRef] [Green Version]
  63. Verbalis, J.G. Vasopressin receptors. In Molecular Mechanisms of Hormone Actions on Behavior, 1st ed.; Etgen, A.M., Pfaff, D.W., Eds.; Academic Press: Cambridge, MA, USA, 2009; pp. 803–810. [Google Scholar]
  64. Jasnic, N.; Djordjevic, J.; Vujovic, P.; Lakic, I.; Djurasevic, S.; Cvijic, G. The effect of vasopressin 1b receptor (V1bR) blockade on HPA axis activity in rats exposed to acute heat stress. J. Exp. Biol. 2013, 216, 2303–2307. [Google Scholar] [CrossRef] [Green Version]
  65. El-Werfali, W.; Toomasian, C.; Maliszewska-Scislo, M.; Li, C.; Rossi, N.F. Haemodynamic and renal sympathetic responses to V1b vasopressin receptor activation within the paraventricular nucleus. Exp. Physiol. 2015, 100, 553–565. [Google Scholar] [CrossRef]
  66. Ahn, D.K.; Kim, K.H.; Ju, J.S.; Kwon, S.; Park, J.S. Microinjection of arginine vasopressin into the central nucleus of amygdala suppressed nociceptive jaw opening reflex in freely moving rats. Brain Res. Bull. 2001, 55, 117–121. [Google Scholar] [CrossRef]
  67. Carter, C.S. The oxytocin-vasopressin pathway in the context of love and fear. Front. Endocrinol. (Lausanne) 2017, 8, 356. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Johnson, Z.V.; Young, L.J. Oxytocin and vasopressin neural networks: Implications for social behavioral diversity and translational neuroscience. Neurosci. Biobehav. Rev. 2017, 76, 87–98. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Watkins, L.R.; Suberg, S.N.; Thurston, C.L.; Culhane, E.S. Role of spinal cord neuropeptides in pain sensitivity and analgesia: Thyrotropin releasing hormone and vasopressin. Brain Res. 1986, 362, 308–317. [Google Scholar] [CrossRef]
  70. Pasquali, R.; Gagliardi, L.; Vicennati, V.; Gambineri, A.; Colitta, D.; Ceroni, L.; Casimirri, F. ACTH and cortisol response to combined corticotropin releasing hormone-arginine vasopressin stimulation in obese males and its relationship to body weight, fat distribution and parameters of the metabolic syndrome. Int. J. Obes. Relat. Metab. Disord. 1999, 23, 419–424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  71. Li, J.D.; Burton, K.J.; Zhang, C.; Hu, S.B.; Zhou, Q.Y. Vasopressin receptor V1a regulates circadian rhythms of locomotor activity and expression of clock-controlled genes in the suprachiasmatic nuclei. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009, 296, R824–R830. [Google Scholar] [CrossRef] [Green Version]
  72. Folny, V.; Raufaste, D.; Lukovic, L.; Pouzet, B.; Rochard, P.; Pascal, M.; Serradeil-Le Gal, C. Pancreatic vasopressin V1b receptors: Characterization in In-R1-G9 cells and localization in human pancreas. Am. J. Physiol. Endocrinol. Metab. 2003, 285, 566–576. [Google Scholar] [CrossRef] [Green Version]
  73. Bichet, D.G.; Arthus, M.F.; Lonergan, M. Platelet vasopressin receptors in patients with congenital nephrogenic diabetes insipidus. Kidney Int. 1991, 39, 693–699. [Google Scholar] [CrossRef] [Green Version]
  74. Baker, C.; Richards, L.J.; Dayan, C.M.; Jessop, D.S. Corticotropin-releasing hormone immunoreactivity in human T and B cells and macrophages: Colocalization with arginine vasopressin. J. Neuroendocrinol. 2003, 15, 1070–1074. [Google Scholar] [CrossRef]
  75. Wiedermann, F.J.; Watzinger, K.; Stichlberger, M.; Joannidis, M.; Kaehler, C.; Lederer, W. Effects of arginine vasopressin on migration and respiratory burst activity in human leukocytes. Open Med. (Wars) 2018, 13, 122–129. [Google Scholar] [CrossRef]
  76. Maggi, M.; Del Carlo, P.; Fantoni, G.; Giannini, S.; Torrisi, C.; Casparis, D.; Massi, G.; Serio, M. Human myometrium during pregnancy contains and responds to V1 vasopressin receptors as well as oxytocin receptors. J. Clin. Endocrinol. Metab. 1990, 70, 1142–1154. [Google Scholar] [CrossRef] [PubMed]
  77. Zhao, N.; Peacock, S.O.; Lo, C.H.; Heidman, L.M.; Rice, M.A.; Fahrenholtz, C.D.; Greene, A.M.; Magani, F.; Copello, V.A.; Martinez, M.J.; et al. Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer. Sci. Transl. Med. 2019, 11, eaaw4636. [Google Scholar] [CrossRef] [PubMed]
  78. Boyd, J.H.; Holmes, C.L.; Wang, Y.; Roberts, H.; Walley, K.R. Vasopressin decreases sepsis-induced pulmonary inflammation through the V2R. Resuscitation 2008, 79, 325–331. [Google Scholar] [CrossRef] [PubMed]
  79. Tamma, R.; Sun, L.; Cuscito, C.; Lu, P.; Corcelli, M.; Li, J.; Colaianni, G.; Moonga, S.S.; Di Benedetto, A.; Grano, M.; et al. Regulation of bone remodeling by vasopressin explains the bone loss in hyponatremia. Proc. Natl. Acad. Sci. USA 2013, 110, 18644–18649. [Google Scholar] [CrossRef] [Green Version]
  80. Phillips, P.A.; Abrahams, J.M.; Kelly, J.M.; Mooser, V.; Trinder, D.; Johnston, C.I. Localization of vasopressin binding sites in rat tissues using specific V1 and V2 selective ligands. Endocrinology 1990, 126, 1478–1484. [Google Scholar] [CrossRef]
  81. Zimmermann-Peruzatto, J.M.; Lazzari, V.M.; de Moura, A.C.; Almeida, S.; Giovenardi, M. Examining the role of vasopressin in the modulation of parental and sexual behaviors. Front. Psychiatry 2015, 6, 130. [Google Scholar] [CrossRef] [Green Version]
  82. Thibonnier, M.; Graves, M.K.; Wagner, M.S.; Auzan, C.; Clauser, E.; Willard, H.F. Structure, sequence, expression, and chromosomal localization of the human v1avasopressin receptor gene. Genomics 1996, 31, 327–334. [Google Scholar] [CrossRef]
  83. Wasilewski, M.A.; Myers, V.D.; Recchia, F.A.; Feldman, A.M.; Tilley, D.G. Arginine vasopressin receptor signaling and functional outcomes in heart failure. Cell. Signal. 2016, 28, 224–233. [Google Scholar] [CrossRef] [Green Version]
  84. Birnbaumer, M. Vasopressin receptors. Trends Endocrinol. Metab. 2000, 11, 406–410. [Google Scholar] [CrossRef]
  85. Machida, K.; Wakamatsu, S.; Izumi, Y.; Yosifovska, T.; Matsuzaki, T.; Nakayama, Y.; Kohda, Y.; Inoue, T.; Saito, H.; Tomita, K.; et al. Downregulation of the V2 vasopressin receptor in dehydration: Mechanisms and role of renal prostaglandin synthesis. Am. J. Phys. Renal Phys. 2007, 292, F1274–F1282. [Google Scholar] [CrossRef]
  86. Sebti, Y.; Rabbani, M.; Sadeghi, H.; Sadeghi, H.M.M.; Sardari, S.; Ghahremani, M.H.; Innamorati, G. Effect of mutations in putative hormone binding sites on V2 vasopressin receptor function. Res. Pharm. Sci. 2015, 10, 259–267. [Google Scholar] [PubMed]
  87. Hoffert, J.D.; Chou, C.L.; Fenton, R.A.; Knepper, M.A. Calmodulin is required for vasopressin-stimulated increase in cyclic AMP production in inner medullary collecting duct. J. Biol. Chem. 2005, 280, 13624–13630. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Robben, J.H.; Knoers, N.V.; Deen, P.M. Regulation of the vasopressin V2 receptor by vasopressin in polarized renal collecting duct cells. Mol. Biol. Cell 2004, 15, 5693–5699. [Google Scholar] [CrossRef] [PubMed]
  89. Agarwal, S.K.; Gupta, A. Aquaporins: The renal water channels. Indian J. Nephrol. 2008, 18, 95–100. [Google Scholar] [CrossRef]
  90. Park, E.J.; Kwon, T.H. A minireview on vasopressin-regulated aquaporin-2 in kidney collecting duct cells. Electrolyte Blood Press. 2015, 13, 1–6. [Google Scholar] [CrossRef] [Green Version]
  91. Olesen, E.T.; Fenton, R.A. Aquaporin-2 membrane targeting: Still a conundrum. Am. J. Physiol. Renal Physiol. 2017, 312, F744–F747. [Google Scholar] [CrossRef] [Green Version]
  92. Friberg, M.A.; Spiess, M.; Rutishauser, J. Degradation of wild-type vasopressin precursor and pathogenic mutants by the proteasome. J. Biol. Chem. 2004, 279, 19441–19447. [Google Scholar] [CrossRef] [Green Version]
  93. Shi, G.; Somlo, D.R.M.; Kim, G.H.; Prescianotto-Baschong, C.; Sun, S.; Beuret, N.; Long, Q.; Rutishauser, J.; Arvan, P.; Spiess, M.; et al. ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis. J. Clin. Investig. 2017, 127, 3897–3912. [Google Scholar] [CrossRef] [Green Version]
  94. Gubbi, S.; Hannah-Shmouni, F.; Verbalis, J.G.; Koch, C.A. Hypophysitis: An update on the novel forms, diagnosis and management of disorders of pituitary inflammation. Best Prac. Res. Clin. Endocrinol. Metab. 2019, 33, 101371. [Google Scholar] [CrossRef]
  95. Bichet, D. Vasopressin receptors in health and disease. Kidney Int. 1996, 49, 1706–1711. [Google Scholar] [CrossRef] [Green Version]
  96. Singh, M.; Dalal, S.; Singh, K. Osteopontin: At the cross-roads of myocyte survival and myocardial function. Life Sci. 2014, 118, 1–6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Nazari, A.; Sadr, S.S.; Faghihi, M.; Imani, A.; Moghimian, M. The cardioprotective effect of different doses of vasopressin (AVP) against ischemia-reperfusion injuries in the anesthetized rat heart. Peptides 2011, 32, 2459–2466. [Google Scholar] [CrossRef] [PubMed]
  98. Zhu, W.; Tilley, D.G.; Myers, V.D.; Tsai, E.J.; Feldman, A.M. Increased vasopressin 1a receptor expression in failing human heart. J. Am. Coll. Cardiol. 2014, 63, 375–376. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Tanoue, A.; Ito, S.; Honda, K.; Oshikawa, S.; Kitagawa, Y.; Koshimizu, T.A.; Mori, T.; Tsujimoto, G. The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions. J. Clin. Investig. 2004, 113, 302–309. [Google Scholar] [CrossRef] [PubMed]
  100. Stevenson, E.L.; Caldwell, H.K. The vasopressin 1b receptor and the neural regulation of social behavior. Horm. Behav. 2012, 61, 277–282. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Mohan, S.R.; Moffett, C.; Thomas, K.G.; Irwin, N.; Flatt, P.R. Vasopressin receptors in islets enhance glucose tolerance, pancreatic beta-cell secretory function, proliferation and survival. Biochimie 2019, 158, 191–198. [Google Scholar] [CrossRef]
  102. Taveau, C.; Chollet, C.; Waeckel, L.; Desposito, D.; Bichet, D.G.; Arthus, M.F.; Magnan, C.; Philippe, E.; Paradis, V.; Foufelle, F.; et al. Vasopressin and hydration play a major role in the development of glucose intolerance and hepatic steatosis in obese rats. Diabetologia 2015, 58, 1081–1090. [Google Scholar] [CrossRef] [Green Version]
  103. Taveau, C.; Chollet, C.; Bichet, D.G.; Velho, G.; Guillon, G.; Corbani, M.; Roussel, R.; Bankir, L.; Melander, O.; Bouby, N. Acute and chronic hyperglycemic effects of vasopressin in normal rats: Involvement of V1a receptors. Am. J. Physiol. Endocrinol. Metab. 2017, 312, E127–E135. [Google Scholar] [CrossRef]
  104. Tashima, Y.; Kohda, Y.; Nonoguchi, H.; Ikebe, M.; Machida, K.; Star, R.A.; Tomita, K. Intranephron localization and regulation of the V1a vasopressin receptor during chronic metabolic acidosis and dehydration in rats. Pflugers Arch. 2001, 442, 652–661. [Google Scholar] [CrossRef]
  105. Martin, N.P.; Lefkowitz, R.J.; Shenoy, S.K. Regulation of V2 vasopressin receptor degradation by agonist-promoted ubiquitination. J. Biol. Chem. 2003, 278, 45954–45959. [Google Scholar] [CrossRef] [Green Version]
  106. Liu, J.; Sharma, N.; Zheng, W.; Ji, H.; Tam, H.; Wu, X.; Manigrasso, M.B.; Sandberg, K.; Verbalis, J.G. Sex differences in vasopressin V2 receptor expression and vasopressin-induced antidiuresis. Am. J. Physiol. Renal Physiol. 2011, 300, F433–F440. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Goncharova, N.D. Stress responsiveness of the hypothalamic-pituitary-adrenal axis: Age-related features of the vasopressinergic regulation. Front. Endocrinol. (Lausanne) 2013, 4, 26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Kashiwazaki, A.; Fujiwara, Y.; Tsuchiya, H.; Sakai, N.; Shibata, K.; Koshimizu, T.A. Subcellular localization and internalization of the vasopressin V1B receptor. Eur. J. Pharmacol. 2015, 765, 291–299. [Google Scholar] [CrossRef] [PubMed]
  109. Birnbaumer, M.; Antaramian, A.; Themmen, A.P.; Gilbert, S. Desensitization of the human V2 vasopressin receptor. Homologous effects in the absence of heterologous desensitization. J. Biol. Chem. 1992, 267, 11783–11788. [Google Scholar] [CrossRef]
  110. Nathanson, M.H.; Burgstahler, A.D.; Orloff, J.J.; Mani, A.; Moyer, M.S. Mechanism of desensitization of the cloned vasopressin V1a receptor expressed in Xenopus oocytes. Am. J. Physiol. Cell Physiol. 1994, 267, C94–C103. [Google Scholar] [CrossRef] [PubMed]
  111. Ancellin, N.; Morel, A. Homologous and heterologous acute desensitization of vasopressin V1a receptor in Xenopus oocytes. Cell. Signal. 1998, 10, 217–223. [Google Scholar] [CrossRef]
  112. Innamorati, G.; Sadeghi, H.M.; Tran, N.T.; Birnbaumer, M. A serine cluster prevents recycling of the V2 vasopressin receptor. Proc. Natl. Acad. Sci. USA 1998, 95, 2222–2226. [Google Scholar] [CrossRef] [Green Version]
  113. Innamorati, G.; Sadeghi, H.M.; Tran, N.T.; Birnbaumer, M. Transient phosphorylation of the V1a vasopressin receptor. J. Biol. Chem. 1998, 273, 7155–7166. [Google Scholar] [CrossRef] [Green Version]
  114. Innamorati, G.; Le Gouill, C.; Balamotis, M.; Birnbaumer, M. The long and the short cycle: Alternative intracellular routes for trafficking of G-protein-coupled receptors. J. Biol. Chem. 2001, 276, 13096–13103. [Google Scholar] [CrossRef] [Green Version]
  115. Ancellin, N.; Preisser, L.; Le Maout, S.; Barbado, M.; Creminon, C.; Corman, B.; Morel, A. Homologous and heterologous phosphorylation of the vasopressin V1a receptor. Cell. Signal. 1999, 11, 743–751. [Google Scholar] [CrossRef]
  116. Bichet, D.G. V2R mutations and nephrogenic diabetes insipidus. Prog. Mol. Biol. Transl. Sci. 2009, 89, 15–29. [Google Scholar] [PubMed]
  117. Bockenhauer, D.; Bichet, D.G. Nephrogenic diabetes insipidus. Curr. Opin. Pediatr. 2017, 29, 199–205. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Bichet, D.G. Genetics in Endocrinology Pathophysiology, diagnosis and treatment of familial nephrogenic diabetes insipidus. Eur. J. Endocrinol. 2020, 183, R29–R40. [Google Scholar] [CrossRef] [PubMed]
  119. Bergmann, C.; Guay-Woodford, L.M.; Harris, P.C.; Horie, S.; Peters, D.J.; Torres, V.E. Polycystic kidney disease. Nat. Rev. Dis. Primers. 2018, 4, 50. [Google Scholar] [CrossRef]
  120. Harris, P.C.; Torres, V.E. Polycystic kidney disease. Annu. Rev. Med. 2009, 60, 321–337. [Google Scholar] [CrossRef]
  121. Bergmann, C.; Senderek, J.; Küpper, F.; Schneider, F.; Dornia, C.; Windelen, E.; Eggermann, T.; Rudnik-Schoneborn, S.; Kirfel, J.; Furu, L.; et al. PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD). Hum. Mut. 2004, 23, 453–463. [Google Scholar] [CrossRef]
  122. Wang, X.; Wu, Y.; Ward, C.J.; Harris, P.C.; Torres, V.E. Vasopressin directly regulates cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 2008, 19, 102–108. [Google Scholar] [CrossRef]
  123. Hughes, J.; Ward, C.J.; Peral, B.; Aspinwall, R.; Clark, K.; San Millan, J.L.; Gamble, V.; Harris, P.C. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat. Genet. 1995, 10, 151–160. [Google Scholar] [CrossRef]
  124. Hanaoka, K.; Qian, F.; Boletta, A.; Bhunia, A.K.; Piontek, K.; Tsiokas, L.; Sukhatme, V.P.; Guggino, W.B.; Germino, G.G. Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents. Nature 2000, 408, 990–994. [Google Scholar] [CrossRef]
  125. Bai, C.X.; Giamarchi, A.; Rodat-Despoix, L.; Padilla, F.; Downs, T.; Tsiokas, L.; Delmas, P. Formation of a new receptor-operated channel by heteromeric assembly of TRPP2 and TRPC1 subunits. EMBO Rep. 2008, 9, 472–479. [Google Scholar] [CrossRef] [Green Version]
  126. Onuchic, L.F.; Furu, L.; Nagasawa, Y.; Hou, X.; Eggermann, T.; Ren, Z.; Bergmann, C.; Senderek, J.; Esquivel, E.; Zeltner, R.; et al. PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. Am. J. Hum. Genet. 2002, 70, 1305–1317. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Ward, C.J.; Hogan, M.C.; Rossetti, S.; Walker, D.; Sneddon, T.; Wang, X.; Kubly, V.; Cunningham, J.M.; Bacallao, R.; Ishibashi, M.; et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat. Genet. 2002, 30, 259–269. [Google Scholar] [CrossRef] [PubMed]
  128. Xiong, H.; Chen, Y.; Yi, Y.; Tsuchiya, K.; Moeckel, G.; Cheung, J.; Liang, D.; Tham, K.; Xu, X.; Chen, X.Z.; et al. A novel gene encoding a TIG multiple domain protein is a positional candidate for autosomal recessive polycystic kidney disease. Genomics 2002, 80, 96–104. [Google Scholar] [CrossRef] [PubMed]
  129. Kim, I.; Fu, Y.; Hui, K.; Moeckel, G.; Mai, W.; Li, C.; Liang, D.; Zhao, P.; Ma, J.; Chen, X.Z. Fibrocystin/polyductin modulates renal tubular formation by regulating polycystin-2 expression and function. J. Am. Soc. Nephrol. 2008, 19, 455–468. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  130. Torres, V.E.; Chapman, A.B.; Devuyst, O.; Gansevoort, R.T.; Perrone, R.D.; Koch, G.; Ouyang, J.; McQuade, R.D.; Blais, J.D.; Czerwiec, F.S.; et al. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N. Engl. J. Med. 2017, 377, 1930–1942. [Google Scholar] [CrossRef] [PubMed]
  131. Torres, V.E.; Harris, P.C. Mechanisms of disease: Autosomal dominant and recessive polycystic kidney diseases. Nat. Rev. Nephrol. 2006, 2, 40–55. [Google Scholar] [CrossRef]
  132. Devuyst, O.; Torres, V.E. Osmoregulation, vasopressin, and cAMP signaling in autosomal dominant polycystic kidney disease. Curr. Opin. Nephrol. Hypertens. 2013, 22, 459–470. [Google Scholar] [CrossRef] [Green Version]
  133. Chebib, F.T.; Sussman, C.R.; Wang, X.; Harris, P.C.; Torres, V.E. Vasopressin and disruption of calcium signalling in polycystic kidney disease. Nat. Rev. Nephrol. 2015, 11, 451–464. [Google Scholar] [CrossRef] [Green Version]
  134. Seeger-Nukpezah, T.; Geynisman, D.M.; Nikonova, A.S.; Benzing, T.; Golemis, E.A. The hallmarks of cancer: Relevance to the pathogenesis of polycystic kidney disease. Nat. Rev. Nephrol. 2015, 11, 515–534. [Google Scholar] [CrossRef] [Green Version]
  135. Nagao, S.; Nishii, K.; Katsuyama, M.; Kurahashi, H.; Marunouchi, T.; Takahashi, H.; Wallace, D.P. Increased water intake decreases progression of polycystic kidney disease in the PCK rat. J. Am. Soc. Nephrol. 2006, 17, 2220–2227. [Google Scholar] [CrossRef] [Green Version]
  136. Reif, G.A.; Yamaguchi, T.; Nivens, E.; Fujiki, H.; Pinto, C.S.; Wallace, D.P. Tolvaptan inhibits ERK-dependent cell proliferation, Cl− secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. Am. J. Physiol. Renal Physiol. 2011, 301, F1005–F1013. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Rinschen, M.M.; Schermer, B.; Benzing, T. Vasopressin-2 receptor signaling and autosomal dominant polycystic kidney disease: From bench to bedside and back again. J. Am. Soc. Nephrol. 2014, 25, 1140–1147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  138. Wu, M.; Yu, S. New insights into the molecular mechanisms targeting tubular channels/transporters in PKD development. Kidney Dis. 2016, 2, 128–135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Pinto, C.S.; Reif, G.A.; Nivens, E.; White, C.; Wallace, D.P. Calmodulin-sensitive adenylyl cyclases mediate AVP-dependent cAMP production and Cl− secretion by human autosomal dominant polycystic kidney cells. Am. J. Physiol. Renal Physiol. 2012, 303, F1412–F1424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  140. Belibi, F.A.; Reif, G.; Wallace, D.P.; Yamaguchi, T.; Olsen, L.; Li, H. Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells. Kidney Int. 2004, 66, 964–973. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  141. Gradilone, S.A.; Masyuk, T.V.; Huang, B.Q.; Banales, J.M.; Lehmann, G.L.; Radtke, B.N.; Stroope, A.; Masyuk, A.I.; Splinter, P.L.; LaRusso, N.F. Activation of Trpv4 reduces the hyperproliferative phenotype of cystic cholangiocytes from an animal model of ARPKD. Gastroenterology 2010, 139, 304–314. [Google Scholar] [CrossRef] [Green Version]
  142. Juul, K.V.; Bichet, D.G.; Nielsen, S.; Nørgaard, J.P. The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors. Am. J. Physiol. Renal Physiol. 2014, 306, F931–F940. [Google Scholar] [CrossRef]
  143. Ishikawa, I.; Maeda, K.; Nakai, S.; Kawaguchi, Y. Gender difference in the mean age at the induction of hemodialysis in patients with autosomal dominant polycystic kidney disease. Am. J. Kidney Dis. 2000, 35, 1072–1075. [Google Scholar] [CrossRef]
  144. Bae, K.T.; Zhou, W.; Shen, C.; Landsittel, D.P.; Wu, Z.; Tao, C.; Chapman, A.B.; Torres, V.E.; Lu, A.S.L.; Mrug, M.; et al. Growth pattern of kidney cyst number and volume in autosomal dominant polycystic kidney disease. Clin. J. Am. Soc. Nephrol. 2019, 14, 823–833. [Google Scholar] [CrossRef]
  145. Mozaffarian, D.; Benjamin, E.J.; Go, A.S.; Arnett, D.K.; Blaha, M.J.; Cushman, M.; de Ferranti, S.; Després, J.P.; Fullerton, H.J.; Howard, V.J.; et al. Heart disease and stroke statistics update: A report from the American Heart Association. Circulation 2015, 131, e29–e322. [Google Scholar]
  146. Ishikawa, S. Arginine vasopressin in heart failure. Circ. J. 2014, 78, 2161–2259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Chen, X.; Lu, G.; Tang, K.; Li, Q.; Gao, X. The secretion patterns and roles of cardiac and circulating arginine vasopressin during the development of heart failure. Neuropeptides 2015, 51, 63–73. [Google Scholar] [CrossRef] [PubMed]
  148. Chen, X.; Hackett, P.D.; DeMarco, A.C.; Feng, C.; Stair, S.; Haroon, E.; Ditzen, B.; Pagnoni, G.; Rilling, J.K. Effects of oxytocin and vasopressin on the neural response to unreciprocated cooperation within brain regions involved in stress and anxiety in men and women. Brain Imaging Behav. 2016, 10, 581–593. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  149. Stewart, J.M.; Zeballos, G.A.; Woolf, P.K.; Dweck, H.S.; Gewitz, M.H. Variable arginine vasopressin levels in neonatal congestive heart failure. J. Am. Coll. Cardiol. 1988, 11, 645–650. [Google Scholar] [CrossRef] [Green Version]
  150. Szmydynger-Chodobska, J.; Zink, B.J.; Chodobski, A. Multiple sites of vasopressin synthesis in the injured brain. J. Cereb. Blood Flow Metab. 2011, 31, 47–51. [Google Scholar] [CrossRef] [Green Version]
  151. Hiroyama, M.; Wang, S.; Aoyagi, T.; Oikawa, R.; Sanbe, A.; Takeo, S.; Tanoue, A. Vasopressin promotes cardiomyocyte hypertrophy via vasopressin V1A receptor in neonatal mice. Eur. J. Pharmacol. 2007, 559, 89–97. [Google Scholar] [CrossRef]
  152. Yang, X.; Zhao, L.; Zheng, Q.; Li, X. Effects of arginine vasopressin on growth of rat cardiac fibroblasts: Role of V1 receptor. J. Cardiovasc. Pharmacol. 2003, 42, 132–135. [Google Scholar] [CrossRef]
  153. Czarzasta, K.; Wojno, O.; Zera, T.; Puchalska, L.; Dobruch, J.; Cudnoch-Jedrzejewska, A. The influence of post-infarct heart failure and high fat diet on the expression of apelin APJ and vasopressin V1a and V1b receptors. Neuropeptides 2019, 78, 101975. [Google Scholar] [CrossRef]
  154. Goldsmith, S.R.; Gheorghiade, M. Vasopressin antagonism in heart failure. J. Am. Coll. Cardiol. 2005, 46, 1786–1791. [Google Scholar] [CrossRef] [Green Version]
  155. Li, X.; Chan, T.O.; Myers, V.; Chowdhury, I.; Zhang, X.Q.; Song, J.; Zhang, J.; Andrel, J.; Funakoshi, H.; Robbins, J.; et al. Controlled and cardiac-restricted overexpression of the arginine vasopressin V1a receptor causes reversible left ventricular dysfunction through Gαq-mediated cell signaling. Circulation 2011, 124, 572–581. [Google Scholar] [CrossRef] [Green Version]
  156. Tilley, D.G.; Zhu, W.; Myers, V.D.; Barr, L.A.; Gao, E.; Li, X.; Song, J.; Carter, R.L.; Makarewich, C.A.; Yu, D.; et al. β-Adrenergic receptor-mediated cardiac contractility is inhibited via vasopressin type 1A-receptor-dependent signaling. Circulation 2014, 130, 1800–1811. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  157. Chen, Y.; Xu, F.; Zhang, L.; Wang, X.; Wang, Y.; Woo, A.Y.H.; Zhu, W. GRK2/β-arrestin mediates arginine vasopressin-induced cardiac fibroblast proliferation. Clin. Exp. Pharmacol. Physiol. 2017, 44, 285–293. [Google Scholar] [CrossRef] [PubMed]
  158. Schrier, R.W.; Abraham, W.T. Hormones and hemodynamics in heart failure. N. Engl. J. Med. 1999, 341, 577–585. [Google Scholar] [CrossRef] [PubMed]
  159. Gheorghiade, M.; Rossi, J.S.; Cotts, W.; Shin, D.D.; Hellkamp, A.S.; Pina, I.L.; Fonarow, G.C.; DeMarco, T.; Pauly, D.F.; Rogers, J.; et al. Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial. Arch. Intern. Med. 2007, 167, 1998–2005. [Google Scholar] [CrossRef]
  160. Xu, Y.J.; Gopalakrishnan, V. Vasopressin increases cytosolic free [Ca2+] in the neonatal rat cardiomyocyte. Circ. Res. 1991, 69, 239–245. [Google Scholar] [CrossRef] [Green Version]
  161. Xu, D.; Martin, P.; Ohara, M.; St John, J.; Pattison, T.; Meng, X.; Morris, K.; Kim, J.K.; Schrier, R.W. Upregulation of aquaporin-2 water channel expression in chronic heart failure rat. J. Clin. Investigat. 1997, 99, 1500–1505. [Google Scholar] [CrossRef] [Green Version]
  162. Brønd, L.; Müllertz, K.M.; Torp, M.; Nielsen, J.; Graebe, M.; Hadrup, N.; Jonassen, T.E.N. Congestive heart failure in rats is associated with increased collecting duct vasopressin sensitivity and vasopressin type 2 receptor re-externalization. Am. J. Physiol. Renal Physiol. 2013, 305, F1547–F1554. [Google Scholar] [CrossRef] [Green Version]
  163. Carter, C.S. Oxytocin pathways and the evolution of human behavior. Annu. Rev. Psychol. 2014, 65, 17–39. [Google Scholar] [CrossRef] [Green Version]
  164. Veenema, A.H.; Neumann, I.D. Central vasopressin and oxytocin release: Regulation of complex social behaviours. Prog. Brain Res. 2008, 170, 261–276. [Google Scholar]
  165. Huber, D.; Veinante, P.; Stoop, R. Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala. Science 2005, 308, 245–248. [Google Scholar] [CrossRef] [Green Version]
  166. Meyer-Lindenberg, A.; Domes, G.; Kirsch, P.; Heinrichs, M. Oxytocin and vasopressin in the human brain: Social neuropeptides for translational medicine. Nat. Rev. Neurosci. 2011, 12, 524–538. [Google Scholar] [CrossRef] [PubMed]
  167. Axelrod, J.; Reisine, T.D. Stress hormones: Their interaction and regulation. Science 1984, 224, 452–459. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  168. Planas, B.; Kolb, P.E.; Raskind, M.A.; Miller, M.A. Sex difference in coexpression by galanin neurons accounts for sexual dimorphism of vasopressin in the bed nucleus of the stria terminalis. Endocrinology 1995, 136, 727–733. [Google Scholar] [CrossRef] [PubMed]
  169. Goodson, J.; Bass, A. Social behavior functions and related anatomical characteristics of vasotocin/vasopressin systems in vertebrates. Brain Res Rev. 2001, 35, 246–265. [Google Scholar] [CrossRef]
  170. Quintana, L.; Pouso, P.; Fabbiani, G.; Macadar, O. A central pacemaker that underlies the production of seasonal and sexually dimorphic social signals: Anatomical and electrophysiological aspects. J. Comp. Physiol. A. Neuroethol. Sens. Neural Behav. Physiol. 2011, 197, 75–88. [Google Scholar] [CrossRef]
  171. Buijs, R.M.; De Vries, G.J.; Van Leeuwen, F.W.; Swaab, D.F. Vasopressin and oxytocin: Distribution and putative functions in the brain. Prog. Brain Res. 1983, 60, 115–122. [Google Scholar]
  172. Antoni, F.A. Vasopressinergic control of pituitary adrenocorticotropin secretion comes of age. Front. Neuroendocrinol. 1993, 14, 76–122. [Google Scholar] [CrossRef]
  173. Leng, G.; Brown, C.H.; Russell, J.A. Physiological pathways regulating the activity of magnocellular neurosecretory cells. Prog. Neurobiol. 1999, 57, 625–655. [Google Scholar] [CrossRef]
  174. Landgraf, R.; Neumann, I.D. Vasopressin and oxytocin release within the brain: A dynamic concept of multiple and variable modes of neuropeptide communication. Front. Neuroendocrinol. 2004, 25, 150–176. [Google Scholar] [CrossRef]
  175. Armstrong, W.E. Hypothalamic supraoptic and paraventricular nuclei. In The Rat Nervous System, 4th ed.; Paxinos, G., Ed.; Academic Press: Amsterdam, The Netherlands, 2015; pp. 295–314. [Google Scholar]
  176. Sofroniew, M.V. Vasopressin and oxytocin in the mammalian brain and spinal cord. Front. Neuroendocrinol. 1983, 40, 1–23. [Google Scholar] [CrossRef]
  177. Albers, H.E. Species, sex and individual differences in the vasotocin/vasopressin system: Relationship to neurochemical signaling in the social behavior neural network. Front. Neuroendocrinol. 2015, 36, 49–71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  178. Wacker, D.; Ludwig, M. The role of vasopressin in olfactory and visual processing. Cell Tissue Res. 2019, 375, 201–215. [Google Scholar] [CrossRef] [PubMed]
  179. Ludwig, M.; Leng, G. Dendritic neuropeptide release and peptide dependent behaviours. Nat. Rev. Neurosci. 2006, 7, 126–136. [Google Scholar] [CrossRef] [PubMed]
  180. Ludwig, M.; Stern, J. Multiple signalling modalities mediated by dendritic exocytosis of oxytocin and vasopressin. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2015, 370, 20140182. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  181. Motoki, K.; Sugiura, M.; Takeuchi, H.; Kotozaki, Y.; Nakagawa, S.; Yokoyama, R.; Kawashima, R. Are plasma oxytocin and vasopressin levels reflective of amygdala activation during the processing of negative emotions? A preliminary study. Front. Psychol. 2016, 7, 480. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  182. Sausville, E.; Carney, D.; Battey, J. The human vasopressin gene is linked to the oxytocin gene and is selectively expressed in a cultured lung cancer cell line. J. Biol. Chem. 1985, 260, 10236–10241. [Google Scholar] [CrossRef]
  183. Acher, R.; Chauvet, J.; Chauvet, M.T. Man and the chimaera. Selective versus neutral oxytocin evolution. Adv. Exp. Med. Biol. 1995, 395, 615–627. [Google Scholar]
  184. Legros, J.J. Inhibitory effect of oxytocin on corticotrope function in humans: Are vasopressin and oxytocin ying-yang neurohormones? Psychoneuroendocrinology 2001, 26, 649–655. [Google Scholar] [CrossRef]
  185. Carter, C.S.; Grippo, A.J.; Pournajafi-Nazarloo, H.; Ruscio, M.G.; Porges, S.W. Oxytocin, vasopressin and sociality. Prog. Brain Res. 2008, 170, 331–336. [Google Scholar]
  186. Neumann, I.D.; Landgraf, R. Balance of brain oxytocin and vasopressin: Implications for anxiety, depression, and social behaviors. Trends Neurosci. 2012, 35, 649–659. [Google Scholar] [CrossRef]
  187. Stoop, R. Neuromodulation by oxytocin and vasopressin. Neuron 2012, 76, 142–159. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  188. Ferris, C. Role of vasopressin in aggressive and dominant/subordinate behaviors. Ann. N. Y. Acad. Sci. 1992, 652, 212–226. [Google Scholar] [CrossRef] [PubMed]
  189. Moore, F.L.; Lowry, C.A. Comparative neuroanatomy of vasotocin and vasopressin in amphibians and other vertebrates. Comp. Biochem. Physiol. 1998, 119, 251–260. [Google Scholar] [CrossRef]
  190. Newman, S.W. The medial extended amygdala in male reproductive behaviour. A node in the mammalian social reproductive behaviour. Ann. N. Y. Acad. Sci. 1999, 877, 242–257. [Google Scholar] [CrossRef]
  191. Engelmann, M.; Wotjak, C.T.; Ebner, K.; Landgraf, R. Behavioural impact of intraseptally released vasopressin and oxytocin in rats. Exp. Physiol. 2000, 85, 125S–130S. [Google Scholar] [CrossRef]
  192. Gilligan, P.; Brenner, S.; Venkatesh, B. Neurone-specific expression and regulation of the puffer fish isotocin and vasotocin genes in transgenic mice. J. Neuroendocrinol. 2003, 15, 1027–1036. [Google Scholar] [CrossRef]
  193. Goodson, J.L. The vertebrate social behavior network: Evolutionary themes and variations. Horm. Behav. 2005, 48, 11–22. [Google Scholar] [CrossRef] [Green Version]
  194. Storm, E.E.; Tecott, L.H. Social circuits: Peptidergic regulation of mammalian social behavior. Neuron 2005, 47, 483–486. [Google Scholar] [CrossRef] [Green Version]
  195. De Vries, G.J.; Panzica, G.C. Sexual differentiation of central vasopressin and vasotocin systems in vertebrates: Different mechanisms, similar endpoints. Neuroscience 2006, 138, 947–955. [Google Scholar] [CrossRef] [Green Version]
  196. Donaldson, Z.R.; Young, L.J. Oxytocin, vasopressin, and the neurogenetics of sociality. Science 2008, 322, 900–904. [Google Scholar] [CrossRef] [Green Version]
  197. Caldwell, H.K.; Aulino, E.A.; Rodriguez, K.M.; Witchey, S.K.; Yaw, A.M. Social context, stress, neuropsychiatric disorders, and the vasopressin 1b receptor. Front. Neurosci. 2017, 11, 567. [Google Scholar] [CrossRef] [PubMed]
  198. Griebel, G.; Holsboer, F. Neuropeptide receptor ligands as drugs for psychiatric diseases: The end of the beginning? Nat. Rev. Drug. Discov. 2012, 11, 462–478. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  199. Wu, N.; Shang, S.; Su, Y. The arginine vasopressin V1b receptor gene and prosociality: Mediation role of emotional empathy. PsyCh J. 2015, 4, 160–165. [Google Scholar] [CrossRef] [PubMed]
  200. Roper, J.; O’Carroll, A.M.; Young, W.; Lolait, S. The vasopressin Avpr1b receptor: Molecular and pharmacological studies. Stress 2011, 14, 98–115. [Google Scholar] [CrossRef]
  201. Barsegyan, A.; Atsak, P.; Hornberger, W.B.; Jacobson, P.B.; Van Gaalen, M.M.; Roozendaal, B. The vasopressin 1b receptor antagonist A-988315 blocks stress effects on the retrieval of object-recognition memory. Neuropsychopharmacology 2015, 40, 1979–1989. [Google Scholar] [CrossRef] [Green Version]
  202. Wersinger, S.R.; Caldwell, H.K.; Christiansen, M.; Young, W.S. Disruption of the vasopressin 1b receptor gene impairs the attack component of aggressive behavior in mice. Genes Brain Behav. 2007, 6, 653–660. [Google Scholar] [CrossRef] [Green Version]
  203. Bosch, O.J. Maternal aggression in rodents: Brain oxytocin and vasopressin mediate pup defence. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2013, 368, 20130085. [Google Scholar] [CrossRef] [Green Version]
  204. Wersinger, S.R.; Ginns, E.I.; O’Carroll, A.M.; Lolait, S.J.; Young III, W.S. Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol. Psychiatry 2002, 7, 975–984. [Google Scholar] [CrossRef] [Green Version]
  205. Wersinger, S.R.; Kelliherb, K.R.; Zufallb, F.; Lolait, S.J.; O’Carroll, A.M.; Young, W.S., III. Social motivation is reduced in vasopressin 1b receptor null mice despite normal performance in an olfactory discrimination task. Horm. Behav. 2004, 46, 638–645. [Google Scholar] [CrossRef] [Green Version]
  206. Ferguson, J.N.; Young, L.J.; Insel, T.R. The neuroendocrine basis of social recognition. Front. Neuroendocrinol. 2002, 23, 200–224. [Google Scholar] [CrossRef] [Green Version]
  207. Bales, K.L.; Kim, A.J.; Lewis-Reese, A.D.; Carter, C.S. Both oxytocin and vasopressin may influence alloparental behavior in male prairie voles. Horm. Behav. 2004, 45, 354–361. [Google Scholar] [CrossRef] [PubMed]
  208. Bielsky, I.; Bao-Hu, S.; Szegda, K.; Westphal, H.; Young, L. Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice. Neuropsychopharmacology 2004, 29, 483–493. [Google Scholar] [CrossRef] [PubMed]
  209. Albers, H.E. The regulation of social recognition, social communication and aggression: Vasopressin in the social behavior neural network. Horm. Behav. 2012, 61, 283–292. [Google Scholar] [CrossRef] [PubMed]
  210. Stemmelin, J.; Lukovic, L.; Salome, N.; Griebel, G. Evidence that the lateral septum is involved in the antidepressant-like effects of the vasopressin V1b receptor antagonist, SSR149415. Neuropsychopharmacology 2005, 30, 35–42. [Google Scholar] [CrossRef] [PubMed]
  211. Frazier, C.R.; Trainor, B.C.; Cravens, C.J.; Whitney, T.K.; Marler, C.A. Paternal behavior influences development of aggression and vasopressin expression in male California mouse offspring. Horm. Behav. 2006, 50, 699–707. [Google Scholar] [CrossRef]
  212. Clipperton-Allen, A.E.; Lee, A.W.; Reyes, A.; Devidze, N.; Phan, A.; Pfaff, D.W.; Choleris, E. Oxytocin, vasopressin and estrogen receptor gene expression in relation to social recognition in female mice. Physiol. Behav. 2012, 105, 915–924. [Google Scholar] [CrossRef] [Green Version]
  213. Wacker, D.W.; Engelmann, M.; Tobin, V.A.; Meddle, S.L.; Ludwig, M. Vasopressin and social odor processing in the olfactory bulb and anterior olfactory nucleus. Ann. N. Y. Acad. Sci. 2011, 1220, 106–116. [Google Scholar] [CrossRef]
  214. Tobin, V.A.; Hashimoto, H.; Wacker, D.W.; Takayanagi, Y.; Langnaese, K.; Caquineau, C.; Noack, J.; Landgraf, R.; Onaka, T.; Leng, G.; et al. An intrinsic vasopressin system in the olfactory bulb is involved in social recognition. Nature 2010, 464, 413–417. [Google Scholar] [CrossRef]
  215. Pineda, R.; Plaisier, F.; Millar, R.P.; Ludwig, M. Amygdala kisspeptin neurons: Putative mediators of olfactory control of the gonadotropic axis. Neuroendocrinology 2017, 104, 223–238. [Google Scholar] [CrossRef] [Green Version]
  216. De Vries, G.J.; Buijs, R.M. The origin of the vasopressinergic and oxytocinergic innervation of the rat brain with special reference to the lateral septum. Brain Res. 1983, 273, 307–317. [Google Scholar] [CrossRef] [Green Version]
  217. Goodson, J.L. Territorial aggression and dawn song are modulated by septal vasotocin and vasoactive intestinal polypeptide in male field sparrows (Spizella pusilla). Horm. Behav. 1998, 34, 67–77. [Google Scholar] [CrossRef] [PubMed]
  218. Goodson, J.L.; Adkins-Regan, E. Effect of intraseptal vasotocin and vasoactive intestinal polypeptide infusions on courtship song and aggression in the male zebra finch (Taeniopygia guttata). J. Neuroendocrinol. 1999, 11, 19–25. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  219. Koolhaas, J.M.; Everts, H.; de Ruiter, A.J.; de Boer, S.F.; Bohus, B. Coping with stress in rats and mice: Differential peptidergic modulation of the amygdala-lateral septum complex. Prog. Brain Res. 1998, 119, 437–448. [Google Scholar] [PubMed]
  220. Pedersen, C.A.; Ascher, J.A.; Monroe, Y.L.; Prange, A.J., Jr. Oxytocin induces maternal behavior in virgin female rats. Science 1982, 216, 648–650. [Google Scholar] [CrossRef]
  221. Pedersen, C.A.; Caldwell, J.D.; Johnson, M.F.; Fort, S.A.; Prange, A.J., Jr. Oxytocin antiserum delays onset of ovarian steroid-induced maternal behavior. Neuropeptide 1985, 6, 175–182. [Google Scholar] [CrossRef]
  222. Pedersen, C.A.; Caldwell, J.D.; Walker, C.; Ayers, G.; Mason, G.A. Oxytocin activates the postpartum onset of rat maternal behavior in the ventral tegmental and medial preoptic areas. Behav. Neurosci. 1994, 108, 1163–1171. [Google Scholar] [CrossRef]
  223. Wang, Z.; Ferris, C.F.; De Vries, G.J. Role of septal vasopressin innervation in paternal behavior in prairie voles (Microtus ochrogaster). Proc. Natl. Acad. Sci. USA 1994, 91, 400–404. [Google Scholar] [CrossRef] [Green Version]
  224. Argiolas, A.; Melis, M.R. Neuropeptides and central control of sexual behaviour from the past to the present: A review. Prog. Neurobiol. 2013, 108, 80–107. [Google Scholar] [CrossRef]
  225. De Vries, G.J.; Al-Shamma, H.A. Sex differences in hormonal responses of vasopressin pathways in the rat brain. J. Neurobiol. 1990, 21, 686–693. [Google Scholar] [CrossRef]
  226. Urban, J.H.; Miller, M.A.; Dorsa, D.M. Dexamethasone-induced suppression of vasopressin gene-expression in the bed nucleus of the stria terminalis and medial amygdala is mediated by changes in testosterone. Endocrinology 1991, 129, 109–116. [Google Scholar] [CrossRef]
  227. De Vries, G.J.; Wang, Z.; Bullock, N.A.; Numan, S. Sex differences in the effects of testosterone and its metabolites on vasopressin messenger RNA levels in the bed nucleus of the stria terminalis of rats. J. Neurosci. 1994, 14, 1789–1794. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  228. Delville, Y.; Mansour, K.M.; Ferris, C.F. Testosterone facilitates aggression by modulating vasopressin receptors in the hypothalamus. Physiol. Behav. 1996, 60, 25–29. [Google Scholar] [CrossRef]
  229. Lebow, M.; Chen, A. Overshadowed by the amygdala: The bed nucleus of the stria terminalis emerges as key to psychiatric disorders. Mol. Psychiatry 2016, 21, 450–463. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  230. De Vries, G.J.; Buijs, R.M.; Swaab, D.F. Ontogeny of the vasopressinergic neurons of the suprachiasmatic nucleus and their extrahypothalamic projections in the rat brain—presence of a sex difference in the lateral septum. Brain Res. 1981, 218, 67–78. [Google Scholar] [CrossRef] [Green Version]
  231. Fink, G.; Rosie, R.; Sheword, W.J.; Thomson, E.; Wilson, H. Steroid control of central neuronal interactions and function. J. Steroid Biochem. Mol. Biol. 1991, 40, 123–132. [Google Scholar] [CrossRef]
  232. De Vries, G.J.; Södersten, P. Sex differences in the brain: The relation between structure and function. Horm. Behav. 2009, 55, 589–596. [Google Scholar] [CrossRef] [Green Version]
  233. Garcia-Villalon, A.L.; Garcia, J.L.; Fernandez, N.; Monge, L.; Gomez, B.; Dieguez, G. Regional differences in the arterial response to vasopressin: Role of endothelial nitric oxide. Br. J. Pharmacol. 1996, 118, 1848–1854. [Google Scholar] [CrossRef]
  234. Rosen, G.J.; De Vries, G.J.; Goldman, S.L.; Goldman, B.D.; Forger, N.G. Distribution of vasopressin in the brain of the eusocial naked mole-rat. J. Comp. Neurol. 2007, 500, 1093–1105. [Google Scholar] [CrossRef]
  235. Qiao, X.; Yan, Y.; Wu, R.; Tai, F.; Hao, P.; Cao, Y.; Wang, J. Sociality and oxytocin and vasopressin in the brain of male and female dominant and subordinate mandarin voles. J. Comp. Physiol. A, Neuroethol. Sens. Neural Behav. Physiol. 2014, 200, 149–159. [Google Scholar] [CrossRef]
  236. Grundwald, N.J.; Benítez, D.P.; Brunton, P.J. Sex-dependent effects of prenatal stress on social memory in rats: A role for differential expression of central vasopressin-1a receptors. J. Neuroendocrinol. 2016, 28. [Google Scholar] [CrossRef]
  237. Hermes, M.; Buijs, R.; Masson-Pévet, M.; Pevet, P. Seasonal changes in vasopressin in the brain of the garden dormouse (Eliomys quercinus L.). J. Comp. Neurol. 1990, 293, 340–346. [Google Scholar] [CrossRef]
  238. Goodson, J.L.; Wilson, L.C.; Schrock, S.E. To flock or fight: Neurochemical signatures of divergent life histories in sparrows. Proc. Natl. Acad. Sci. USA 2012, 109, 10685–10692. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  239. Bamshad, M.; Novak, M.A.; Vries, G.J. Sex and species differences in the vasopressin innervation of sexually naive and parental prairie voles, Microtus ochrogaster and meadow voles, Microtus pennsylvanicus. J. Neuroendocrinol. 1993, 5, 247–255. [Google Scholar] [CrossRef] [PubMed]
  240. Kozorovitskiy, Y.; Hughes, M.; Lee, K.; Gould, E. Fatherhood affects dendritic spines and vasopressin V1a receptors in the primate prefrontal cortex. Nat. Neurosci. 2006, 9, 1094–1095. [Google Scholar] [CrossRef] [PubMed]
  241. Lambert, K.G.; Franssen, C.L.; Bardi, M.; Hampton, J.E.; Hainley, L.; Karsner, S.; Tu, E.B.; Hyer, M.M.; Crockett, A.; Baranova, A.; et al. Characteristic neurobiological patterns differentiate paternal responsiveness in two Peromyscus species. Brain Behav. Evol. 2011, 77, 159–175. [Google Scholar] [CrossRef] [PubMed]
  242. Perea-Rodriguez, J.; Takahashi, E.; Amador, T.; Hao, R.; Saltzman, W.; Trainor, B. Effects of reproductive experience on central expression of progesterone, oestrogen α, oxytocin and vasopressin receptor mRNA in male California mice (Peromyscus californicus). J. Neuroendocrinol. 2015, 27, 245–252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  243. Tsuji, T.; Allchorne, A.J.; Zhang, M.; Tsuji, C.; Tobin, V.A.; Pineda, R.; Raftogianni, A.; Stern, J.E.; Grinevich, V.; Leng, G.; et al. Vasopressin casts light on the suprachiasmatic nucleus. J. Physiol. 2017, 595, 3497–3514. [Google Scholar] [CrossRef] [PubMed]
  244. Gizowski, C.; Zaelzer, C.; Bourque, C. Clock-driven vasopressin neurotransmission mediates anticipatory thirst prior to sleep. Nature 2016, 537, 685–688. [Google Scholar] [CrossRef] [PubMed]
  245. Gizowski, C.; Zaelzer, C.; Bourque, C.W. Activation of organum vasculosum neurones and water intake in mice by vasopressin neurones in the suprachiasmatic nucleus. J. Neuroendocrinol. 2018, 30, e12577. [Google Scholar] [CrossRef] [PubMed]
  246. Ebstein, R.P.; Israel, S.; Lerer, E.; Uzefovsky, F.; Shalev, I.; Gritsenko, I.; Riebold, M.; Salomon, S.; Yirmiya, N. Arginine vasopressin and oxytocin modulate human social behavior. Ann. N. Y. Acad. Sci. 2009, 1167, 87–102. [Google Scholar] [CrossRef]
  247. Crockford, C.; Deschner, T.; Ziegler, T.E.; Wittig, R.M. Endogenous peripheral oxytocin measures can give insight into the dynamics of social relationships: A review. Front. Behav. Neurosci. 2014, 8, 68. [Google Scholar] [CrossRef] [PubMed]
  248. Feldman, R.; Monakhov, M.; Pratt, M.; Ebstein, R.P. Oxytocin pathway genes: Evolutionary ancient system impacting on human affiliation, sociality, and psychopathology. Biol. Psychiatry 2016, 79, 174–184. [Google Scholar] [CrossRef] [PubMed]
  249. Petrovic, P.; Kalisch, R.; Singer, T.; Dolan, R.J. Oxytocin attenuates affective evaluations of conditioned faces and amygdala activity. J. Neurosci. 2008, 28, 6607–6615. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  250. Scheele, D.; Striepens, N.; Gunturkun, O.; Deutschlander, S.; Maier, W.; Kendrick, K.M.; Hurlemann, R. Oxytocin modulates social distance between males and females. J. Neurosci. 2012, 32, 16074–16079. [Google Scholar] [CrossRef] [PubMed]
  251. Preckel, K.; Scheele, D.; Kendrick, K.M.; Maier, W.; Hurlemann, R. Oxytocin facilitates social approach behavior in women. Front. Behav. Neurosci. 2014, 8, 191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  252. King, L.B.; Walum, H.; Inoue, K.; Eyrich, N.W.; Young, L.J. Variation in the oxytocin receptor gene predicts brain region-specific expression and social attachment. Biol. Psychiatry 2016, 80, 160–169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  253. Brunnlieb, C.; Münte, T.F.; Tempelmann, C.; Heldmann, M. Vasopressin modulates neural responses related to emotional stimuli in the right amygdala. Brain Res. 2013, 1499, 29–42. [Google Scholar] [CrossRef]
  254. Brunnlieb, C.; Nave, G.; Camerer, C.F.; Schosser, S.; Vogt, B.; Münte, T.F.; Heldmann, M. Vasopressin increases human risky cooperative behavior. Proc. Nat. Acad. Sci. USA 2016, 113, 2051–2056. [Google Scholar] [CrossRef] [Green Version]
  255. Rilling, J.K.; Demarco, A.C.; Hackett, P.D.; Chen, X.; Gautam, P.; Stair, S.; Haroon, E.; Thompson, R.; Ditzen, B.; Patel, R.; et al. Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology 2014, 39, 237–248. [Google Scholar] [CrossRef] [Green Version]
  256. Coccaro, E.F.; Kavoussi, R.J.; Hauger, R.L.; Cooper, T.B.; Ferris, C.F. Cerebrospinal fluid vasopressin levels: Correlates with aggression and serotonin function in personality-disordered subjects. Arch. Gen. Psychiatry 1998, 55, 708–714. [Google Scholar] [CrossRef] [Green Version]
  257. Dalton, K.M.; Nacewicz, B.M.; Johnstone, T.; Schaefer, H.S.; Gernsbacher, M.A.; Goldsmith, H.H.; Alexander, A.L.; Davidson, R.J. Gaze fixation and the neural circuitry of face processing in autism. Nat. Neurosci. 2005, 8, 519–526. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  258. Dalton, K.M.; Nacewicz, B.M.; Alexander, A.L.; Davidson, R.J. Gaze-fixation, brain activation, and amygdala volume in unaffected siblings of individuals with autism. Biol. Psychiatry 2007, 61, 512–520. [Google Scholar] [CrossRef] [PubMed]
  259. Hadjikhani, N.; Joseph, R.M.; Snyder, J.; Tager-Flusberg, H. Abnormal activation of the social brain during face perception in autism. Hum. Brain Mapp. 2007, 28, 441–449. [Google Scholar] [CrossRef] [PubMed]
  260. Bookheimer, S.Y.; Wang, A.T.; Scott, A.; Sigman, M.; Dapretto, M. Frontal contributions to face processing differences in autism: Evidence from fMRI of inverted face processing. J. Int. Neuropsychol. Soc. 2008, 14, 922–932. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  261. Meyer-Lindenberg, A.; Kolachana, B.; Gold, B.; Olsh, A.; Nicodemus, K.K.; Mattay, V.; Dean, M.; Weinberger, D.R. Genetic variants in AVPR1A linked to autism predict amygdala activation and personality traits in healthy humans. Mol. Psychiatry 2009, 14, 968–975. [Google Scholar] [CrossRef]
  262. Zink, C.F.; Stein, J.L.; Kempf, L.; Hakimi, S.; Meyer-Lindenberg, A. Vasopressin modulates medial prefrontal cortex-amygdala circuitry during emotion processing in humans. J. Neurosci. 2010, 30, 7017–7022. [Google Scholar] [CrossRef] [PubMed]
  263. Dai, L.; Carter, C.S.; Ying, J.; Bellugi, U.; Pournajafi-Nazarloo, H.; Korenberg, J.R. Oxytocin and vasopressin are dysregulated in Williams Syndrome, a genetic disorder affecting social behavior. PLoS ONE 2012, 7, e38513. [Google Scholar] [CrossRef] [Green Version]
  264. Rubin, L.H.; Carter, C.S.; Bishop, J.R.; Pournajafi-Nazarloo, H.; Harris, M.S.; Hill, S.K.; Reilly, J.L.; Sweeney, J.A. Peripheral vasopressin but not oxytocin relates to severity of acute psychosis in women with acutely-ill untreated first-episode psychosis. Schizophr. Res. 2013, 146, 138–143. [Google Scholar] [CrossRef] [Green Version]
  265. El-Ansfary, A.; Al-Ayadhi, L. GABAergic/glutamatergic imbalance relative to excessive neuroinflammation in autism spectrum disorders. J. Neuroinflamm. 2014, 11, 189. [Google Scholar] [CrossRef]
  266. Guastella, A.J.; Hickie, I.B. Oxytocin treatment, circuitry, and autism: A critical review of the literature placing oxytocin into the autism context. Biol. Psychiatry 2016, 79, 234–242. [Google Scholar] [CrossRef]
  267. Zhang, R.; Zhang, H.F.; Han, J.S.; Han, S.P. Genes related to oxytocin and arginine-vasopressin pathways: Associations with autism spectrum disorders. Neurosci. Bull. 2017, 33, 238–246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  268. Cataldo, I.; Azhari, A.; Esposito, G. A review of oxytocin and arginine-vasopressin receptors and their modulation of autism spectrum disorder. Front. Mol. Neurosci. 2018, 11, 27. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  269. Rubin, L.H.; Carter, C.S.; Bishop, J.R.; Pournajafi-Nazarloo, H.; Drogos, L.L.; Hill, S.K.; Reilly, J.L.; Sweeney, J.A. Reduced levels of vasopressin and reduced behavioral modulation of oxytocin in psychotic disorders. Schizophr. Bull. 2014, 40, 1374–1384. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  270. Selten, J.P.; Cantor-Graae, E. Social defeat: Risk factor for schizophrenia? Br. J. Psychiatry 2005, 187, 101–102. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  271. Albers, H.E.; Karom, M.; Smith, D. Serotonin and vasopressin interact in the hypothalamus to control communicative behavior. Neuroreport 2002, 13, 931–933. [Google Scholar] [CrossRef]
  272. Galfi, M.; Radacs, M.; Juhasz, A.; Laszlo, F.; Molnar, A.; Laszlo, F.A. Serotonin-induced enhancement of vasopressin and oxytocin secretion in rat neurohypophyseal tissue culture. Regul. Pept. 2005, 127, 225–231. [Google Scholar] [CrossRef]
  273. Bachner-Melman, R.; Dina, C.; Zohar, A.H.; Constantini, N.; Lerer, E.; Hoch, S.; Sella, S.; Nemanov, L.; Gritsenko, I.; Lichtenberg, P.; et al. AVPR1a and SLC6A4 gene polymorphisms are associated with creative dance performance. PLoS Genet. 2005, 1, e42. [Google Scholar] [CrossRef] [Green Version]
  274. Pezawas, L.; Meyer-Lindenberg, A.; Drabant, E.M.; Verchinski, B.A.; Munoz, K.E.; Kolachana, B.S.; Egan, M.F.; Mattay, V.S.; Hariri, A.R.; Weinberger, D.R. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: A genetic susceptibility mechanism for depression. Nat. Neurosci. 2005, 8, 828–834. [Google Scholar] [CrossRef]
  275. Meyer-Lindenberg, A.; Buckholtz, J.W.; Kolachana, B.; Hariri, A.R.; Pezawas, L.; Blasi, G.; Wabnitz, A.; Honea, R.; Verchinski, B.; Callicott, J.H.; et al. Neural mechanisms of genetic risk for impulsivity and violence in humans. Proc. Natl. Acad. Sci. USA 2006, 103, 6269–6274. [Google Scholar] [CrossRef] [Green Version]
  276. Grace, S.A.; Rossell, S.L.; Heinrichs, M.; Kordsachia, C.; Labuschagne, I. Oxytocin and brain activity in humans: A systematic review and coordinate based meta-analysis of functional MRI studies. Psychoneuroendocrinology 2018, 96, 6–24. [Google Scholar] [CrossRef]
  277. Lefevre, A.; Hurlemann, R.; Grinevich, V. Imaging neuropeptide effects on human brain function. Cell Tissue Res. 2018, 375, 279–286. [Google Scholar] [CrossRef] [PubMed]
  278. Brydges, N.M.; Hall, J.; Best, C.; Rule, L.; Watkin, H.; Drake, A.J.; Lewis, C.; Thomas, K.L.; Hall, J. Childhood stress impairs social function through AVP-dependent mechanisms. Transl. Psychiatry 2019, 9, 330. [Google Scholar] [CrossRef] [PubMed]
  279. Meinlschmidt, G.; Heim, C. Sensitivity to intranasal oxytocin in adult men with early parental separation. Biol. Psychiatry 2007, 61, 1109–1111. [Google Scholar] [CrossRef] [PubMed]
  280. Insel, T.R.; Young, L.J. The neurobiology of attachment. Nat. Rev. Neurosci. 2001, 2, 129–136. [Google Scholar] [CrossRef] [PubMed]
  281. Goossens, L.; Kukolja, J.; Onur, O.A.; Fink, G.R.; Maier, W.; Griez, E.; Schruers, K.; Hurlemann, R. Selective processing of social stimuli in the superficial amygdala. Hum. Brain Mapp. 2009, 30, 3332–3338. [Google Scholar] [CrossRef]
  282. Rogers, C.N.; Ross, A.P.; Sahu, S.P.; Siegel, E.R.; Dooyema, J.M.; Cree, M.A.; Stopa, E.G.; Young, L.J.; Rilling, J.K.; Albers, H.E.; et al. Oxytocin-and arginine vasopressin-containing fibers in the cortex of humans, chimpanzees, and rhesus macaques. Am. J. Primatol. 2018, 80, e22875. [Google Scholar] [CrossRef]
  283. Uddin, L.Q.; Nomi, J.S.; Hébert-Seropian, B.; Ghaziri, J.; Boucher, O. Structure and function of the human insula. J. Clin. Neurophysiol. 2017, 34, 300–306. [Google Scholar] [CrossRef]
  284. Thibonnier, M.; Graves, M.K.; Wagner, M.S.; Chatelain, N.; Soubrier, F.; Corvol, P.; Willard, H.F.; Jeunemaitre, X. Study of V1-vascular vasopressin receptor gene microsatellite polymorphisms in human essential hypertension. J. Mol. Cell. Cardiol. 2000, 32, 557–564. [Google Scholar] [CrossRef]
  285. Kim, S.J.; Young, L.J.; Gonen, D.; Veenstra-VanderWeele, J.; Courchesne, R.; Lord, C.; Leventhal, B.L.; Cook, E.H., Jr.; Insel, T.R. Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism. Mol. Psychiatry 2002, 7, 503–507. [Google Scholar] [CrossRef] [Green Version]
  286. Wassink, T.H.; Piven, J.; Vieland, V.J.; Pietila, J.; Goedken, R.J.; Folstein, S.E.; Sheffield, V.C. Examination of AVPR1a as an autism susceptibility gene. Mol. Psychiatry 2004, 9, 968–972. [Google Scholar] [CrossRef]
  287. Hammock, E.A.; Young, L.J. Microsatellite instability generates diversity in brain and sociobehavioral traits. Science 2005, 308, 1630–1634. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  288. Mabry, K.E.; Streatfeild, C.A.; Keane, B.; Solomon, N.G. Avpr1a length polymorphism is not associated with either social or genetic monogamy in free-living prairie voles. Anim. Behav. 2011, 81, 11–18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  289. Walum, H.; Westberg, L.; Henningson, S.; Neiderhiser, J.M.; Reiss, D.; Igl, W.; Ganiban, J.M.; Spotts, E.L.; Pedersen, N.L.; Eriksson, E.; et al. Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans. Proc. Natl Acad. Sci. USA 2008, 105, 14153–14156. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  290. Guastella, A.J.; Kenyon, A.R.; Unkelbach, C.; Alvares, G.A.; Hickie, I.B. Arginine vasopressin selectively enhances recognition of sexual cues in male humans. Psychoneuroendocrinology 2011, 36, 294–297. [Google Scholar] [CrossRef]
  291. Zink, C.F.; Meyer-Lindenberg, A. Human neuroimaging of oxytocin and vasopressin in social cognition. Horm. Behav. 2012, 61, 400–409. [Google Scholar] [CrossRef] [Green Version]
  292. Ben-Efraim, Y.J.; Wasserman, D.; Wasserman, J.; Sokolowski, M. Family-based study of AVPR1B association and interaction with stressful life events on depression and anxiety in suicide attempts. Neuropsychopharmacology 2013, 38, 1504–1511. [Google Scholar] [CrossRef] [Green Version]
  293. Aspé-Sánchez, M.; Moreno, M.; Rivera, M.I.; Rossi, A.; Ewer, J. Oxytocin and vasopressin receptor gene polymorphisms: Role in social and psychiatric traits. Front. Neurosci. 2016, 9, 510. [Google Scholar] [CrossRef] [Green Version]
  294. Jobst, A.; Dehning, S.; Ruf, S.; Notz, T.; Buchheim, A.; Henning-Fast, K.; Meißner, D.; Meyer, S.; Bondy, B.; Müller, N.; et al. Oxytocin and vasopressin levels are decreased in the plasma of male schizophrenia patients. Acta Neuropsychiatr. 2014, 26, 347–355. [Google Scholar] [CrossRef] [Green Version]
  295. Born, J.; Lange, T.; Kern, W.; McGregor, G.P.; Bickel, U.; Fehm, H.L. Sniffing neuropeptides: A transnasal approach to the human brain. Nat. Neurosci. 2002, 5, 514–516. [Google Scholar] [CrossRef]
  296. Glover, G.H. Overview of functional magnetic resonance imaging. Neurosurg. Clin. N. Am. 2011, 22, 133–139. [Google Scholar] [CrossRef] [Green Version]
  297. Thompson, R.; Gupta, S.; Miller, K.; Mills, S.; Orr, S. The effects of vasopressin on human facial responses related to social communication. Psychoneuroendocrinology 2004, 29, 35–48. [Google Scholar] [CrossRef]
  298. Thompson, R.R.; George, K.; Walton, J.C.; Orr, S.P.; Benson, J. Sex-specific influences of vasopressin on human social communication. Proc. Natl. Acad. Sci. USA 2006, 103, 7889–7894. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  299. Rilling, J.K.; DeMarco, A.C.; Hackett, P.D.; Thompson, R.; Ditzen, B.; Patel, R.; Pagnoni, G. Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men. Psychoneuroendocrinology 2012, 37, 447–461. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  300. Van Anders, S.M.; Goodson, J.L.; Kingsbury, M.A. Beyond “oxytocin= good”: Neural complexities and the flipside of social bonds. Arch. Sex. Behav. 2013, 42, 1115–1118. [Google Scholar] [CrossRef] [PubMed]
  301. Feng, C.; DeMarco, A.C.; Haroon, E.; Rilling, J.K. Neuroticism modulates the effects of intranasal vasopressin treatment on the neural response to positive and negative social interactions. Neuropsychologia 2015, 73, 108–115. [Google Scholar] [CrossRef] [Green Version]
  302. Jiang, L.; Sheng, Y.; Feng, X.; Wu, J. The effects and safety of vasopressin receptor agonists in patients with septic shock: A meta-analysis and trial sequential analysis. Crit. Care. 2019, 23, 91. [Google Scholar] [CrossRef] [Green Version]
  303. Chan, W.Y.; Wo, N.C.; Stoev, S.T.; Cheng, L.L.; Manning, M. Discovery and design of novel and selective vasopressin and oxytocin agonists and antagonists: The role of bioassays. Exp. Physiol. 2000, 85, 7S–18S. [Google Scholar] [CrossRef]
  304. Rondon-Berrios, H.; Berl, T. Vasopressin receptor antagonists: Characteristics and clinical role. Best Pract. Res. Clin. Endocrinol. Metab. 2016, 30, 289–303. [Google Scholar] [CrossRef]
  305. Narayen, G.; Mandal, S.N. Vasopressin receptor antagonists and their role in clinical medicine. Indian J. Endocrinol. Metab. 2012, 16, 183–191. [Google Scholar] [CrossRef]
  306. Wu, M.Y.; Chen, T.T.; Chen, Y.C.; Tarng, D.C.; Wu, Y.C.; Lin, H.H.; Tu, Y.K. Effects and safety of oral tolvaptan in patients with congestive heart failure: A systematic review and network meta-analysis. PLoS ONE 2017, 12, e0184380. [Google Scholar] [CrossRef] [Green Version]
  307. Farah, J.; Daifallah, S.; Zmily, H.; Ghali, J.K. An overview of satavaptan: A selective V2 receptor antagonist. Therapy 2010, 7, 409–422. [Google Scholar] [CrossRef]
  308. Rangarajan, B.; Binoy, V.; Hingmire, S.S.; Noronha, V. Tolvaptan. South Asian J. Cancer 2014, 3, 182–184. [Google Scholar] [CrossRef] [PubMed]
  309. Di Mise, A.; Venneri, M.; Ranieri, M.; Centrone, M.; Pellegrini, L.; Tamma, G.; Valenti, G. Lixivaptan, a new generation diuretic, counteracts vasopressin-induced aquaporin-2 trafficking and function in renal collecting duct cells. Int. J. Mol. Sci. 2019, 21, 183. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  310. Ali, F.; Raufi, A.M.; Washington, B.; Ghali, J.K. Conivaptan: A dual receptor vasopressin V1a/V2 antagonist. Cardiovasc. Drug Rev. 2007, 25, 261–279. [Google Scholar]
  311. Finley, J.J.; Konstam, M.A.; Udelson, J.E. Arginine vasopressin antagonists for the treatment of heart failure and hyponatremia. Circulation 2008, 118, 410–421. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  312. Bolognani, F.; Del valle, R.M.; Squassante, L.; Wandel, C.; Derks, M.; Murtagh, L. A phase 2 clinical trial of a vasopressin V1a receptor antagonist shows improved adaptive behaviors in men with autism spectrum disorder. Sci. Transl. Med. 2019, 11, eaat7838. [Google Scholar] [CrossRef] [PubMed]
  313. Schnider, P.; Bissantz, C.; Bruns, A.; Dolente, C.; Goetschi, E.; Jakob-Roetne, R.; Kunnecke, B.; Mueggler, T.; Muster, W.; Parrott, N.; et al. Discovery of balovaptan, a vasopressin 1a receptor antagonist for the treatment of autism spectrum disorder. J. Med. Chem. 2020, 63, 1511–1525. [Google Scholar] [CrossRef]
  314. Steinwall, M.; Bossmar, T.; Brouard, R.; Laudanski, T.; Olofsson, P.; Urban, R.; Wolff, K.; Le-Fur, G.; Akerlund, M. The effect of relcovaptan (SR 49059), an orally active vasopressin V1a receptor antagonist, on uterine contractions in preterm labor. Gynecol. Endocrinol. 2005, 20, 104–109. [Google Scholar] [CrossRef]
  315. Decaux, G.; Soupart, A.; Vassart, G. Non-peptide arginine-vasopressin antagonists: The vaptans. Lancet. 2008, 371, 1624–1632. [Google Scholar] [CrossRef]
  316. Serradeil-Le Gal, C.; Wagnon, J.; Tonnerre, B.; Roux, R.; Garcia, G.; Griebel, G.; Aulombard, A. An overview of SSR149415, a selective nonpeptide vasopressin V(1b) receptor antagonist for the treatment of stress-related disorders. CNS Drug Rev. 2005, 11, 53–68. [Google Scholar]
  317. Schule, C.; Baghai, T.C.; Eser, D.; Rupprecht, R. Hypothalamic–pituitary–adrenocortical system dysregulation and new treatment strategies in depression. Exp. Rev. Neurother. 2009, 9, 1005–1019. [Google Scholar] [CrossRef] [PubMed]
  318. Rihakova, L.; Quiniou, C.; Hamdan, F.F.; Kaul, R.; Brault, S.; Hou, X.; Lahaie, I.; Sapieha, P.; Hamel, D.; Shao, Z.; et al. VRQ397 (CRAVKY): A novel noncompetitive V2 receptor antagonist. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009, 297, R1009–R1018. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  319. Yamamura, Y.; Nakamura, S.; Itoh, S.; Hirano, T.; Onogawa, T.; Yamashita, T.; Yamada, Y.; Tsujimae, M.; Aoyama, M.; Kotosai, K.; et al. OPC-41061, a highly potent human vasopressin V2-receptor antagonist: Pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J. Pharmacol. Exp. Ther. 1998, 287, 860–867. [Google Scholar] [PubMed]
  320. Miyazaki, T.; Fujiki, H.; Yamamura, Y.; Nakamura, S.; Mori, T. Tolvaptan, an orally active vasopressin V2-receptor antagonist—pharmacology and clinical trials. Cardiovasc. Drug Rev. 2007, 25, 1–13. [Google Scholar] [CrossRef]
  321. Torres, V.E.; Chapman, A.B.; Devuyst, O.; Gansevoort, R.T.; Grantham, J.J.; Higashihara, E.; Perrone, R.D.; Krasa, H.B.; Ouyang, J.; Czerwiec, F.S. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 2012, 367, 2407–2418. [Google Scholar] [CrossRef] [Green Version]
  322. Pharos. Available online: (accessed on 16 October 2020).
  323. Albright, J.D.; Reich, M.F.; Delos Santos, E.G.; Dusza, J.P.; Sum, F.W.; Venkatesan, A.M.; Coupet, J.; Chan, P.S.; Ru, X.; Mazandarani, H.; et al. 5-Fluoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c]-[1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]benzamide (VPA-985): An orally active arginine vasopressin antagonist with selectivity for V2 receptors. J. Med. Chem. 1998, 41, 2442–2444. [Google Scholar] [CrossRef]
  324. Ku, E.; Nobakht, N.; Campese, V.M. Lixivaptan: A novel vasopressin receptor antagonist. Drug Eval. 2009, 18, 657–662. [Google Scholar] [CrossRef]
  325. Serradeil-Le Gal, C.; Lacour, C.; Valette, G.; Garcia, G.; Foulon, L.; Galindo, G.; Bankir, L.; Pouzet, B.; Guillon, G.; Barberis, C.; et al. Characterization of SR121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist. J. Clin. Investig. 1996, 98, 2729–2738. [Google Scholar] [CrossRef]
  326. Bernat, A.; Hoffman, P.; Dumas, A.; Serradeil-le Gal, C.; Raufaste, D.; Herbert, J.M. V2 receptor antagonism of DDAVP-induced release of hemostasis factors in conscious dogs. J. Pharmacol. Exp. Ther. 1997, 282, 597–602. [Google Scholar]
  327. Serradeil-Le Gal, C.; Raufaste, D.; Double-Cazanave, E.; Guillon, G.; Garcia, C.; Pascal, M.; Maffrand, J.P. Binding properties of a selective tritiated vasopressin V2 receptor antagonist, [3H]-SR121463. Kidney Int. 2000, 56, 1613–1622. [Google Scholar] [CrossRef] [Green Version]
  328. Serradeil-Le Gal, C. An overview of SR121463, a selective non-peptide vasopressin V(2) receptor antagonist. Cardiovasc. Drug Rev. 2001, 19, 201–214. [Google Scholar] [PubMed]
  329. Gines, P.; Wong, F.; Watson, H.; Milutinovic, S.; Ruiz del Arbol, L.; Olteanu, D. Effects of satavaptan, a selective vasopressin V(2) receptor antagonist, on ascites and serum sodium in cirrhosis with hyponatremia: A randomized trial. Hepatology 2008, 48, 204–213. [Google Scholar] [CrossRef] [PubMed]
  330. Yatsu, T.; Tomura, Y.; Tahara, A.; Wada, K.; Kusayama, T.; Tsukada, J.; Tokioka, T.; Uchida, W.; Inagaki, O.; Iizumi, Y.; et al. Cardiovascular and renal effects of conivaptan hydrochloride (YM087), a vasopressin V1A and V2 receptor antagonist, in dogs with pacing-induced congestive heart failure. Eur. J. Pharmacol. 1999, 376, 239–246. [Google Scholar] [CrossRef]
  331. Wada, K.; Fujimori, A.; Matsukawa, U.; Arai, Y.; Sudoh, K.; Yatsu, T.; Sasamata, M.; Miyata, K. Intravenous administration of conivaptan hydrochloride improves cardiac hemodynamics in rats with myocardial infarction-induced congestive heart failure. Eur. J. Pharmacol. 2005, 507, 145–151. [Google Scholar] [CrossRef] [PubMed]
  332. Crombie, A.L.; Antrilli, T.M.; Campbell, B.A.; Crandall, D.L.; Failli, A.A.; He, Y.; Kern, J.C.; Moore, W.J.; Nogle, L.M.; Trybulski, E.J. Synthesis and evaluation of azabicyclo[3.2.1]octane derivatives as potent mixed vasopressin antagonists. Bioorg. Med. Chem. Lett. 2010, 20, 3742–3745. [Google Scholar] [CrossRef]
  333. Serradeil-Le Gal, C.; Wagnon, J.; Simiand, J.; Griebel, G.; Lacour, C.; Guillon, G.; Barberis, C.; Brossard, G.; Soubrie, P.; Nisato, D.; et al. Characterization of (2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide (SSR149415), a selective and orally active vasopressin V1b receptor antagonist. J. Pharmacol. Exp. Ther. 2002, 300, 1122–1130. [Google Scholar]
  334. Ratni, H.; Rogers-Evans, M.; Bissantz, C.; Grundschober, C.; Moreau, J.L.; Schuler, F.; Fischer, H.; Alvarez Sanchez, R.; Schnider, P. Discovery of highly selective brain-penetrant vasopressin 1a antagonists for the potential treatment of autism via a chemogenomic and scaffold hopping approach. J. Med. Chem. 2015, 58, 2275–2289. [Google Scholar] [CrossRef]
  335. Akerlund, M.; Bossmar, T.; Brouard, R.; Kostrzewska, A.; Laudanski, T.; Lemancewicz, A.; Serradeil-Le Gal, C.; Steinwall, M. Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women. Br. J. Obstet. Gynaecol. 1999, 106, 1047–1053. [Google Scholar] [CrossRef]
  336. Cotte, N.; Balestre, M.N.; Aumelas, A.; Mahé, E.; Phalipou, S.; Morin, D.; Hibert, M.; Manning, M.; Durroux, T.; Barberis, C.; et al. Conserved aromatic residues in the transmembrane region VI of the V1a vasopressin receptor differentiate agonist vs. antagonist ligand binding. Eur. J. Biochem. 2000, 267, 4253–4263. [Google Scholar] [CrossRef]
  337. Griffante, C.; Green, A.; Curcuruto, O.; Haslam, C.P.; Dickinson, B.A.; Arban, R. Selectivity of d[Cha4]AVP and SSR149415 at human vasopressin and oxytocin receptors: Evidence that SSR149415 is a mixed vasopressin V1b/oxytocin receptor antagonist. Br. J. Pharmacol. 2005, 146, 744–751. [Google Scholar] [CrossRef]
  338. Yamamura, Y.; Ogawa, H.; Yamashita, H.; Chihara, T.; Miyamoto, H.; Nakamura, S.; Onogawa, T.; Yamashita, T.; Hosokawa, T.; Mori, T.; et al. Characterization of a novel aquaretic agent, OPC-31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist. Br. J. Pharmacol. 1992, 105, 787–791. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  339. Cotte, N.; Balestre, M.N.; Phalipou, S.; Hibert, M.; Manning, M.; Barberis, C.; Mouillac, B. Identification of residues responsible for the selective binding of peptide antagonists and agonists in the V2 vasopressin receptor. J. Biol. Chem. 1998, 273, 29462–29468. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  340. Yamaguchi, K.; Shijubo, N.; Kodama, T.; Mori, K.; Sugiura, T.; Kuriyama, T.; Kawahara, M.; Shinkai, T.; Iguchi, H.; Sakurai, M. Clinical implication of the antidiuretic hormone (ADH) receptor antagonist mozavaptan hydrochloride in patients with ectopic ADH syndrome. Jpn. J. Clin. Oncol. 2011, 41, 148–152. [Google Scholar] [PubMed]
  341. Rai, A.; Whaley-Connell, A.; McFarlane, S.; Sowers, J.R. Hyponatremia, arginine vasopressin dysregulation, and vasopressin receptor antagonism. Am. J. Nephrol. 2006, 26, 579–589. [Google Scholar] [CrossRef] [PubMed]
  342. Torres, V.E.; Wang, X.; Qian, Q.; Somlo, S.; Harris, P.C.; Gattone, V.H., II. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat. Med. 2004, 10, 363–364. [Google Scholar] [CrossRef]
  343. Meijer, E.; Gansevoort, R.T.; De Jong, P.E.; van der Wal, A.M.; Leonhard, W.N.; de Krey, S.R.; van den Born, J.; Mulder, G.M.; van Goor, H.; Struck, J.; et al. Therapeutic potential of vasopressin V2 receptor antagonist in a mouse model for autosomal dominant polycystic kidney disease: Optimal timing and dosing of the drug. Nephrol. Dial. Transplant. 2011, 26, 2445–2453. [Google Scholar] [CrossRef] [Green Version]
  344. Wang, X.; Gattone II, V.; Harris, P.C.; Torres, V.E. Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat. J. Am. Soc. Nephrol. 2005, 16, 846–851. [Google Scholar] [CrossRef] [Green Version]
  345. Torres, V.E.; Chapman, A.B.; Devuyst, O.; Gansevoort, R.T.; Perrone, R.D.; Dandurand, A.; Ouyang, J.; Czerwiec, F.S.; Blais, J.D. Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: The TEMPO 4:4 Trial. Nephrol. Dial. Transplant 2018, 33, 477–489. [Google Scholar] [CrossRef] [Green Version]
  346. Watkins, P.B.; Lewis, J.H.; Kaplowitz, N.; Alpers, D.H.; Blais, J.D.; Smotzer, D.M.; Krasa, H.; Ouyang, J.; Torres, V.E.; Czerwiec, F.S.; et al. Clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: Analysis of clinical trials database. Drug Saf. 2015, 38, 1103–1113. [Google Scholar] [CrossRef] [Green Version]
  347. Sans-Atxer, L.; Joly, D. Tolvaptan in the treatment of autosomal dominant polycystic kidney disease: Patient selection and special considerations. Int. J. Nephrol. Renovasc. Dis. 2018, 11, 41–51. [Google Scholar] [CrossRef] [Green Version]
  348. Zhang, Z.Y.; Wang, Z.M.; Huang, Y. Polycystic liver disease: Classification, diagnosis, treatment process, and clinical management. World J. Hepatol. 2020, 12, 72–83. [Google Scholar] [CrossRef] [PubMed]
  349. Correll, C.U.; Manu, P.; Olshanskiy, V.; Napolitano, B.; Kane, J.M.; Malhotra, A.K. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA 2009, 302, 1765–1773. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  350. Parker, K.J.; Oztan, O.; Libove, R.A.; Mohsin, N.; Karhson, D.S.; Sumiyoshi, R.D.; Summers, J.E.; Hinman, K.E.; Motonaga, K.S.; Phillips, J.M.; et al. A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism. Sci. Transl. Med. 2019, 11, eaau7356. [Google Scholar] [CrossRef] [PubMed]
  351. Noskov, V.B.; Larina, I.M.; Nichiporuk, I.A.; Pastushkova, L.K.; Vasilieva, G. Evaluation of synthetic antidiuretic hormone as a corrective substance following a head-down tilt. Hum. Physiol. 2012, 38, 781–785. [Google Scholar] [CrossRef]
  352. Kamperis, K.; Van Herzeele, C.; Rittig, S.; Walle, J.V. Optimizing response to desmopressin in patients with monosymptomatic nocturnal enuresis. Pediatric. Nephrol. 2017, 32, 217–226. [Google Scholar]
  353. Leone, M.; Albanese, J.; Delmas, A.; Chaabane, W.; Garnier, F.; Martin, C. Terlipressin in catecholamine resistant septic shock patients. Shock 2004, 22, 314–319. [Google Scholar] [CrossRef]
  354. Sarin, S.K.; Sharma, P. Terlipressin: An asset for hepatologists! Hepatology 2011, 54, 724–728. [Google Scholar] [CrossRef]
  355. Scarpati, G.; Piazza, O. Vasopressin vs terlipressin in treatment of refractory shock. Transl. Med. UniSa. 2013, 5, 22–27. [Google Scholar]
  356. Jamil, K.; Pappas, S.C.; Devarakonda, K.R. In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V1 and V2. J. Exp. Pharmacol. 2018, 10, 1–7. [Google Scholar] [CrossRef] [Green Version]
  357. Olgart, L.; Gazelius, B. Effects of adrenaline and felypressin (octapressin) on blood flow and sensory nerve activity in the tooth. Acta Odontol. Scand. 1977, 35, 69–75. [Google Scholar] [CrossRef]
  358. Cecanho, R.; De Luca Jr, L.A.; Ranali, J. Cardiovascular effects of felypressin. Anesth. Prog. 2006, 53, 119–125. [Google Scholar] [CrossRef]
  359. Bronzo, A.L.A.; Cardoso, C.G.; Ortega, K.C.; Mion, D. Felypressin increases blood pressure during dental procedures in hypertensive patients. Arq. Bras. Cardiol. 2012, 99, 724–731. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  360. Manning, M.; Misicka, A.; Olma, A.; Bankowski, K.; Stoev, S.; Chini, B.; Durroux, T.; Mouillac, B.; Corbani, M.; Guillon, G. Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics. J. Neuroendocrinol. 2012, 24, 609–628. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Figure 1. AVP (arginine vasopressin) synthesis and structure. (A) The hypothalamic neurosecretory neurons synthesize the pre-pro-hormone precursor called pre-pro-AVP or AVP-neurophysin-copeptin. The signal peptide is cleaved by a signalase in the endoplasmic reticulum to form pro-pressinphysin. Copeptin is glycosylated and cleaved by an endopeptidase in the Golgi [8,35,45]. Such endopeptidase also separates the pro-AVP vasopressinyl-Gly-Lys-Arg peptide from neurophysin, and pro-AVP is enclosed in vesicles. The C-terminal arginine and lysine are trimmed by carboxypeptidase E and the newly exposed C-terminal glycine is oxidized by glycine monooxygenase into hydroxyl-glycine. Finally, a lyase converts hydroxyl-glycine is into an amide group which subsequently reacts with glyoxylic acid to yield AVP [45]. (B) AVP structure. Note the cyclic structure and primary amide (NH2).
Figure 1. AVP (arginine vasopressin) synthesis and structure. (A) The hypothalamic neurosecretory neurons synthesize the pre-pro-hormone precursor called pre-pro-AVP or AVP-neurophysin-copeptin. The signal peptide is cleaved by a signalase in the endoplasmic reticulum to form pro-pressinphysin. Copeptin is glycosylated and cleaved by an endopeptidase in the Golgi [8,35,45]. Such endopeptidase also separates the pro-AVP vasopressinyl-Gly-Lys-Arg peptide from neurophysin, and pro-AVP is enclosed in vesicles. The C-terminal arginine and lysine are trimmed by carboxypeptidase E and the newly exposed C-terminal glycine is oxidized by glycine monooxygenase into hydroxyl-glycine. Finally, a lyase converts hydroxyl-glycine is into an amide group which subsequently reacts with glyoxylic acid to yield AVP [45]. (B) AVP structure. Note the cyclic structure and primary amide (NH2).
Biomedicines 09 00089 g001
Figure 2. Intracellular response to AVP in renal tubular epithelial cells. AVP binds to the V2R G-protein coupled receptor on the basolateral membrane, which activates adenylyl-cyclase (AC). Produced cAMP activates protein kinase A (PKA), which phosphorylates the AQP2 water channels stored in vesicular compartments. This promotes apical membrane relocation and increased transmembrane water transport (modified after [95]).
Figure 2. Intracellular response to AVP in renal tubular epithelial cells. AVP binds to the V2R G-protein coupled receptor on the basolateral membrane, which activates adenylyl-cyclase (AC). Produced cAMP activates protein kinase A (PKA), which phosphorylates the AQP2 water channels stored in vesicular compartments. This promotes apical membrane relocation and increased transmembrane water transport (modified after [95]).
Biomedicines 09 00089 g002
Figure 3. V2R and AVP signaling in normal and autosomal dominant polycystic kidney disease (ADPKD) renal tubule epithelial cells. In normal cells, AVP binding to V2R promotes dissociation of the trimeric Gs into its α and βγ subunits. The α subunit triggers adenylyl cyclase (AC)-mediated cAMP synthesis, which activates PKA and phosphorylates AQP2. Phospho-AQP2 is shuttled to the apical cell membrane and water reabsorption increased. In ADPKD (red type), reduced Ca2+ release from the ER and impaired Ca2+ import from polycystin 2 at the primary cilia elevate intracellular cAMP (dashed), which in turn increases fluid excretion. Resulting dehydration triggers AVP release from the pituitary. Furthermore, higher than normal intracellular cAMP in ADPKD boosts Cl transport via the cystic fibrosis transmembrane conductance regulator (CFTR) channel that contributes to cystic cell proliferation and chloride-dependent fluid secretion.
Figure 3. V2R and AVP signaling in normal and autosomal dominant polycystic kidney disease (ADPKD) renal tubule epithelial cells. In normal cells, AVP binding to V2R promotes dissociation of the trimeric Gs into its α and βγ subunits. The α subunit triggers adenylyl cyclase (AC)-mediated cAMP synthesis, which activates PKA and phosphorylates AQP2. Phospho-AQP2 is shuttled to the apical cell membrane and water reabsorption increased. In ADPKD (red type), reduced Ca2+ release from the ER and impaired Ca2+ import from polycystin 2 at the primary cilia elevate intracellular cAMP (dashed), which in turn increases fluid excretion. Resulting dehydration triggers AVP release from the pituitary. Furthermore, higher than normal intracellular cAMP in ADPKD boosts Cl transport via the cystic fibrosis transmembrane conductance regulator (CFTR) channel that contributes to cystic cell proliferation and chloride-dependent fluid secretion.
Biomedicines 09 00089 g003
Figure 4. AVP-V1aR signaling contributes to weaker myocardial contractions and cardiac remodeling in heart failure (HF). (A) AVP binding to V1aR during HF activates Gαq protein-mediated signaling, which amplifies IP3 signaling and triggers Ca2+ release (dashed) from the sarcoplasmic reticulum (SR). Prolonged Ca2+ mobilization leads to myocardial hypertrophy. (B) Gαq-independent signaling promotes GRK recruitment to the plasma membrane (PM) decreasing catecholamine-β adrenergic receptor (βAR) activation and Ca2+ mobilization. When prolonged, this condition impairs myocardial contractions.
Figure 4. AVP-V1aR signaling contributes to weaker myocardial contractions and cardiac remodeling in heart failure (HF). (A) AVP binding to V1aR during HF activates Gαq protein-mediated signaling, which amplifies IP3 signaling and triggers Ca2+ release (dashed) from the sarcoplasmic reticulum (SR). Prolonged Ca2+ mobilization leads to myocardial hypertrophy. (B) Gαq-independent signaling promotes GRK recruitment to the plasma membrane (PM) decreasing catecholamine-β adrenergic receptor (βAR) activation and Ca2+ mobilization. When prolonged, this condition impairs myocardial contractions.
Biomedicines 09 00089 g004
Table 1. AVP receptor function and expression.
Table 1. AVP receptor function and expression.
Target TissueReceptorFunctionReferences
Kidney—Macula densa, intermediate, distal and collector tubulesV2RSignal transduction, AQP2 shuttling to cell surface and water permeability, AQP2 mRNA synthesis, intracellular cAMP regulation[14,53,54,55,56]
Kidney—Mesangial cells, efferent arterioles, renal tubulesV1aRVasoconstriction[57,58,59]
Vascular Smooth MuscleV1aRVasoconstriction, myocardial hypertrophy, V1aR mRNA upregulation, hypertension[53,54,58,62]
Brain—Anterior PituitaryV1bRACTH secretion, stimulation of endocrine response to stress[17,53,63,64,65]
Brain—diffused expressionV1aRRegulation of emotional and adaptive behaviors, pain[66,67,68,69]
Brain—HPA axis (adrenal cortex)V1aRCortisol synthesis and secretion[70]
Brain—SCNV1aRCircadian rhythm[71]
Brain—Cerebellum (rats) V2RUnknown[55]
PancreasV1bRGlucagon release, intracellular Ca2+ regulation, cell proliferation[54,72]
Blood—PlateletsV1aRPlatelet aggregation[53,73]
Blood—LeukocytesV1aRChemotaxis, chemokine and antibody production[74,75]
MyometriumV1aRUterine contraction[53,76]
ProstateV1aRUnknown, causative upregulation in castration resistant prostate cancer[18,77]
Skeletal muscleV1aRUnknown[18]
BoneV2RBone remodeling[79]
Cervical ganglion
HPA: hypothalamic–pituitary–adrenal, ACTH: adrenocorticotropic hormone, SCN: suprachiasmatic nucleus.
Table 2. AVP receptor antagonists.
Table 2. AVP receptor antagonists.
AVP Receptor AntagonistsChemistryBinding Affinity & MoARoute of Administration, Dosage & PhysiologyReference(s)
Biomedicines 09 00089 i001
Empirical formula: C26H25ClN3O2Chemical nomenclature: N[4 -(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1-benzazepine-1-carbonyl)-3-methylphenyl]-2-methylbenzamideBinds V2R (pKi: 8.9–9.4) with 30-fold higher affinity than V1aR in vivo.
Reduces water reabsorption (renal collecting ducts), promotes aquaresis.
15–60 mg/day
Reduced rate of renal function decline, edema, body weight and serum Na2+ levels.
Biomedicines 09 00089 i002
Empirical formula: C27H21ClFN3O2
Chemical nomenclature: N-[3-chloro-4-(6,11-dihydropyrrolo[2,1-c][1,4]benzodiazepine-5-carbonyl)phenyl]-5-fluoro-2-methylbenzamide
Binds V2R (pKi: 8.9–9.2) with 100-fold higher affinity than V1aR in vivo.
Prevents translocation and localization of AQP2 to renal collecting ducts, promotes aquaresis.
30–150 mg/day or 1–10 mg/kg
Biomedicines 09 00089 i003
Empirical formula: C32H26N4O2
Chemical nomenclature:
N-tert-butyl-4-[5′-ethoxy-4-(2-morpholin-4ylethoxy)-2′oxospiro [cyclohexane-1,3′-indole]-1′-yl]sulfonyl-3-methoxybenzamide
Binds V2R (pKi: 8.4–9.3) with 112-fold greater affinity than V1aR in vivo.
Aquaretic, similar to tolvaptan.
5–25 mg/day
Biomedicines 09 00089 i004
Empirical formula: C33H45N3O8S
Chemical nomenclature:
N-[4-(2-methyl-4,5-dihydro-3H-imidazo [4,5-d][1]benzazepine-6-carbonyl)phenyl]-2-phenylbenzamide
High affinity for both V1aR (pKi: 9.37) and V2R (pKi: 9.44) in vivo.
V1aR: reduces Ca2+ mobilization and kinase activity (cardiac tissue), reduces myocardium hypertrophy.
V2R: promotes aquaresis similar to tolvaptan.
Oral & intravenous
20–40 mg/day or 0.003–0.1 mg/kg
Biomedicines 09 00089 i005
Empirical formula: C30H32ClN3O8S
Chemical nomenclature:
Binding affinity for V1bR (pKi: 5.9) in vivo.
Normalizes ACTH hypersecretion in response to stress stimuli.
3–30 mg/day
Potential anxiolytic and anti-depressant.
Biomedicines 09 00089 i006
Empirical formula: C22H24ClN5O
Chemical nomenclature:
8-chloro-5-methyl-1-(4-pyridin-2-yloxycyclohexyl)-4,6-dihydro-[1,2,4] triazolo[4,3a][1,4]benzodiazepine
Binding affinity for V1aR (pKd: 5.0, Ki: 1nM) in vivo. Oral
10 mg/day
Improved Vineland II adaptive behavior scales.
Biomedicines 09 00089 i007
Empirical formula: C28H27Cl2N5O7S
Chemical nomenclature:
(2S)-1-[(2R,3S)-5-chloro -3-(2-chlorophenyl)-1-(3,4-dimethoxyphenyl) sulfonyl-3-hydroxy-2H-indole-2-carbonyl] pyrrolidine-2-carboxamide
Binding affinity for V1aR (pKi: 8.1) in vivo.
Promotes vasodilation (vascular bed).
400 mg/day
Potential for treatment of Raynaud’s syndrome and regulation of uterine contractions in preterm labor.
Biomedicines 09 00089 i008
Empirical formula: C27H29N3O2
Chemical nomenclature:
Binding affinity for V2R (pKi: 8.03) in vivo.
30 mg/day or 1–30 mg/kg
Chemical structures retrieved from PubChem NIH.
Table 3. AVP synthetic analogs.
Table 3. AVP synthetic analogs.
AVP & Synthetic AnalogsChemistryBinding Affinity & MoARoute of Administration, Dosage & PhysiologyReference(s)
AVP Biomedicines 09 00089 i009Empirical formula: C44H61N13O12S2
Chemical nomenclature:
Binds V1aR (pKi: 9.59), V1bR (pKi: 9.31) and V2R (pKi: 8.92) with high affinity.
MoA: See text for details.
Oral, intravenous & intranasal
24–32 IU/day
Desmopressin Biomedicines 09 00089 i010Empirical formula: C46H64N14O12S2
Chemical nomenclature:
Binding affinity for V2R (pKi: 8.3).
Induces AQP2 apical translo-cation (renal collecting duct) and water reabsorption.
Oral & intranasal
0.2–0.6 mg/day
Need frequent medical follow-up.
Terlipressin Biomedicines 09 00089 i011Empirical formula: C52H74N16O15S2
Chemical nomenclature:
Binding affinity for both V1aR (1.1 × 10−6 Ki moles) and V2R (6.9 × 10−6 Ki moles).
V1aR: induces splanchnic and renal vasocon-striction, reduces portal pressure.
V2R: increases apical AQP2 and water retention.
1–2 mg/day as needed.
Increased mean arterial pressure, decreased heart rate and improved renal function.
Felypressin Biomedicines 09 00089 i012Empirical formula: C46H65N13O11S2
Chemical nomenclature:
Binding affinity for V1aR (21 units/mg).
Induces smooth muscle contraction (vascular bed).
240 ng/kg
Less antidiuretic effects than AVP.
Chemical structures retrieved from PubChem NIH.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Sparapani, S.; Millet-Boureima, C.; Oliver, J.; Mu, K.; Hadavi, P.; Kalostian, T.; Ali, N.; Avelar, C.M.; Bardies, M.; Barrow, B.; et al. The Biology of Vasopressin. Biomedicines 2021, 9, 89.

AMA Style

Sparapani S, Millet-Boureima C, Oliver J, Mu K, Hadavi P, Kalostian T, Ali N, Avelar CM, Bardies M, Barrow B, et al. The Biology of Vasopressin. Biomedicines. 2021; 9(1):89.

Chicago/Turabian Style

Sparapani, Samantha, Cassandra Millet-Boureima, Joshua Oliver, Kathy Mu, Pegah Hadavi, Tamar Kalostian, Nazifa Ali, Carla Maria Avelar, Marion Bardies, Brenton Barrow, and et al. 2021. "The Biology of Vasopressin" Biomedicines 9, no. 1: 89.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop