Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine

The neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are strongly involved in the regulation of social cognition and behavior. Behavioral studies in humans relying on the intranasal administration of the peptides demonstrate the influence of OXT and AVP on social interactions, e.g., attachment, interpersonal trust, and cooperative behavior, as well as emotion recognition, visual attention and social memory, indicating that OXT and AVP contribute to the processing of social cues. Clinical studies suggest that altered OXT signaling in particular may play a pathophysiological role in mental and developmental disorders characterized by social dysfunction, such as autism, borderline personality disorder, schizophrenia, and social anxiety disorder. This article summarizes recent findings on OXT and AVP effects in healthy humans and patients and addresses potential therapeutical options in the treatment of mental disorders.

Central vasopressin and oxytocin release: regulation of complex social behaviours

Oxytocin, vasopressin, and human social behavior

We used a number of receptor antagonists to determine which receptors mediate the effect of arginine vasopressin (AVP) and oxytocin (OT) on insulin release. We found that OT (10(-7) M) and AVP (10(-8) M) increased insulin release from the perfused rat pancreas with similar magnitude. The antagonist with potent V1b receptor-blocking activity, dP[Tyr(Me)2]AVP (10(-7) M), abolished the effect of OT and AVP, whereas the highly selective OT receptor antagonist L-366,948 (10(-6) M) did not change the effect of OT, nor did a V1a receptor antagonist, d(CH2)5[Tyr(Me)2]AVP (10(-7) M), change the effect of AVP. The insulin-releasing potency of OT was estimated as 9-fold less than that of AVP in RINm5F cells. Selected AVP and OT antagonists were used to study their antagonism on AVP- and OT-induced insulin release from RINm5F cells, and the order of potencies of antagonists was estimated as dP[Tyr(Me)2]AVP > d(CH2)5[D-Phe2,Ile4]AVP > SR-49059 > d(CH2)5[Tyr(Me)2]AVP > desGly9d(CH2)5[Tyr(Et)2]VAVP (WK-3-6) approximately L-366,948. These results were consistent with the V1b receptor antagonistic activities of the antagonists. d[D-3-Pal]VP, a V1b receptor agonist, increased insulin release dose dependently (10(-9) to 10(-6) M), and this effect was antagonized by dP[Tyr(Me)2]AVP but not by WK-3-6 (10(-6) M). These results suggested that the stimulatory effect of both OT and AVP on insulin release from beta-cells may be mediated by V1b, but not by V1a or OT receptors.

Central oxytocin (OXT) has anxiolytic and pro-social properties both in humans and rodents, and has been proposed as a therapeutic option for anxiety and social dysfunctions. Here, we utilized a mouse model of social fear conditioning (SFC) to study the effects of OXT on social fear, and to determine whether SFC causes alterations in central OXT receptor (OXTR) binding and local OXT release. Central infusion of OXT, but not arginine vasopressin, prior to social fear extinction training completely abolished social fear expression in an OXTR-mediated fashion without affecting general anxiety or locomotion. SFC caused increased OXTR binding in the dorso-lateral septum (DLS), central amygdala, dentate gyrus, and cornu ammunis 1, which normalized after social fear extinction, suggesting that these areas form part of a brain network involved in the development and neural support of social fear. Microdialysis revealed that the increase in OXT release observed in unconditioned mice within the DLS during social fear extinction training was attenuated in conditioned mice. Consequently, increasing the availability of local OXT by infusion of OXT into the DLS reversed social fear. Thus, alterations in the brain OXT system, including altered OXTR binding and OXT release within the DLS, play an important role in SFC and social fear extinction. Thus, we suggest that the OXT system is adversely affected in disorders associated with social fear, such as social anxiety disorder and reinstalling an appropriate balance of the OXT system may alleviate some of the symptoms.

Plasma oxytocin (OT) and arginine vasopressin (AVP) are associated with individual differences in emotional responses and behaviors. The amygdala is considered to be an important brain region for regulating emotion-based behavior, with OT and AVP modulating activity in the amygdala during the processing of negative emotions. In particular, increased OT levels may diminish amygdala activation (anxiolytic effects) and enhanced AVP levels may augment amygdala activation (anxiogenic effects) when negative emotions are processed. A growing body of research has shown that the effects of OT and AVP are modulated by sex: the aforementioned anxiolytic effects of OT and the anxiogenic effects of AVP occur in men, but not in women. However, we have little knowledge regarding the biological mechanisms underlying OT and AVP plasma levels or their respective anxiogenic and anxiolytic effects; similarly, little is known about the causes and nature of sex differences related to these neuropeptides and their effects on emotional processing. In the current study, we focused on the neural functions associated with the biological mechanisms underlying such effects. We hypothesized that amygdala activation would correlate with trait plasma OT (anxiolytic effects) and AVP (anxiogenic effects) levels because the amygdala is thought to affect the coordinated release of these neuropeptides following affective experiences. We further hypothesized that the effects would be modulated by sex. We assessed 51 participants (male and female) using a paradigm involving negative emotion in conjunction with functional magnetic resonance imaging and measurements of plasma OT and AVP levels. We determined that increased plasma AVP levels were positively associated with amygdala activation (anxiogenic effects) in men, but not in women. These findings highlight the potential underlying neural mechanisms of plasma AVP levels in men.

Extrahypothalamic vasopressin and oxytocin in the human brain; presence of vasopressin cells in the bed nucleus of the stria terminalis

Oxytocin (OT) and arginine-vasopressin (AVP) are involved in the regulation of complex social behaviors across a wide range of taxa. Despite this, little is known about the neuroanatomy of the OT and AVP systems in most non-human primates, and less in humans. The effects of OT and AVP on social behavior, including aggression, mating, and parental behavior, may be mediated primarily by the extensive connections of OT- and AVP-producing neurons located in the hypothalamus with the basal forebrain and amygdala, as well as with the hypothalamus itself. However, OT and AVP also influence social cognition, including effects on social recognition, cooperation, communication, and in-group altruism, which suggests connectivity with cortical structures. While OT and AVP V1a receptors have been demonstrated in the cortex of rodents and primates, and intranasal administration of OT and AVP has been shown to modulate cortical activity, there is to date little evidence that OT-and AVP-containing neurons project into the cortex. Here, we demonstrate the existence of OT- and AVP-containing fibers in cortical regions relevant to social cognition using immunohistochemistry in humans, chimpanzees, and rhesus macaques. OT-immunoreactive fibers were found in the straight gyrus of the orbitofrontal cortex as well as the anterior cingulate gyrus in human and chimpanzee brains, while no OT-immunoreactive fibers were found in macaque cortex. AVP-immunoreactive fibers were observed in the anterior cingulate gyrus in all species, as well as in the insular cortex in humans, and in a more restricted distribution in chimpanzees. This is the first report of OT and AVP fibers in the cortex in human and non-human primates. Our findings provide a potential mechanism by which OT and AVP might exert effects on brain regions far from their production site in the hypothalamus, as well as potential species differences in the behavioral functions of these target regions.

Oxytocin (OXT) is a neuropeptide hormone that plays a central role in numerous physiological and socio-emotional processes. Similar to arginine vasopressin (AVP), it is synthesized in the supraoptic and paraventricular hypothalamic nuclei and released both centrally and peripherally. Peripherally, OXT regulates uterine contractions during childbirth and milk ejection during lactation, metabolism, bone health, and cardiovascular functions. Centrally, it modulates social behavior, influencing trust, empathy, stress regulation, and emotional processing. Despite its close connection to AVP, the clinical significance of OXTDeficiency has only recently gained attention, particularly in patients with hypothalamic or pituitary damage with concomitant AVP-Deficiency. OXT-Deficiency may contribute to various neuropsychological symptoms seen in these patients, including social dysfunction, anxiety disorders, and reduced quality of life. However, a major challenge lies in accurately measuring OXT and thereby diagnosing a potential OXT-Deficiency. Basal plasma levels are unreliable, and most studied provocation tests only stimulate to a limited degree; hence, stronger provocation tests (e.g., using MDMA) and new surrogate parameters such as neurophysin I (NP-I) are gaining traction. Preliminary evidence from case reports and one small study suggests that intranasal OXT administration in patients with hypothalamic disorders may have beneficial effects on social behavior and emotion recognition. However, there is a clear need for larger, well-designed clinical trials, and several trials are currently underway to investigate the therapeutic potential of OXT in patients with AVP-Deficiency. OXT is also being explored as a possible treatment option in psychiatric conditions such as autism spectrum disorder, borderline personality disorder, and social anxiety disorder, with controversial results so far.

It has previously been shown that arginine vasopressin (AVP) exerts a direct stimulatory action on rat adrenocortical cells. In the present study, we have investigated the possible effect of AVP on cortisol secretion by normal human adrenocortical tissue. The occurrence of endogenous AVP in the human adrenal gland has been studied by means of the indirect immunofluorescence technique. The presence of AVP-containing cells was observed in both cortex and medulla. The action of AVP on corticosteroidogenesis has been investigated in vitro using a perifusion system technique coupled to a specific RIA for cortisol. Graded doses of AVP (from 10(-11)-10(-9) M) increased cortisol secretion in a dose-dependent manner (ED50, 4.5 x 10(-11) M). AVP also induced a significant stimulation of cortisol release from acutely dispersed adrenocortical cells. Prolonged administration of AVP (3 h) induced a rapid and transient increase in cortisol output, followed by a gradual decline in cortisol secretion. Repeated pulses of AVP, given at 90-min intervals, resulted in reproducible stimulations of cortisol output. Selective agonists and antagonists have been used to determine the type of receptor involved in the response of adrenocortical cells to AVP. Oxytocin at doses up to 10(-7) M had virtually no effect on cortisol secretion. The stimulatory effect of AVP was blocked by the V1 antagonist [beta-mercapto-beta,beta-cyclopentamethylene propionyl 1, OMe-Tyr2, Arg8]AVP. In contrast, the V2 antagonist [d(CH2)5D-Phe2,Ile4,Ala9-NH2]AVP did not affect the response of the adrenal gland to AVP. The selective V2 agonist [deamino-Cys1,D-Arg8]AVP did not mimic the stimulatory effect of AVP on cortisol secretion. Taken together, these results suggest that AVP, locally released by intracortical cells, may act as a paracrine factor to stimulate adrenal steroidogenesis in man. The effect of AVP on cortisol secretion appears to be mediated through activation of typical V1 receptors.

Social dysfunction in the neurodevelopmental model of schizophrenia in male and female rats: Behavioural and biochemical studies

Introduction In the central nervous system, arginine vasopressin (AVP) and oxytocin (OT) stimulate neural networks that regulate social behaviors, including social attachment, aggression, and complex social cognition. AVP and OT are neuropeptides that are expressed in the social behavioral network and bind to G‐protein coupled receptors, stimulating cellular signaling patterns that ultimately affect social behaviors at the organismal level. Consensus mammalian AVP and OT sequences are highly conserved. In addition to sequence homology between AVP and OT, there is ~85% structural homology between the OT receptor (OTR) and vasopressin 1a receptor (V1aR) resulting in significant cross‐reactivity between the ligands and receptors. Perturbations in OT and/or OT receptor expression results in social behavioral deficits, and is associated with a number of psychopathologies including autism spectrum disorder, schizophrenia, anxiety, and depression. Methods The human neuroblastoma derived SH‐SY5Y cell line demonstrates morphological characteristics of neurons including neurites and formation of functional synapses, endogenously expresses OTR, and is often used as an in vitro model for human neurons. Functional assays were performed using Fluo8‐AM to measure ligand‐induced Ca 2+ mobilization and FLIPR Membrane Potential (FMP) assays were performed to assess ligand‐induced hyperpolarization. To assess effects on neurite outgrowth, cells were treated with logarithmic doses of AVP and OT for 24 hours, fixed and stained with phalloidin and DAPI. Results In SH‐SY5Y cells, OT was more potent than AVP at both ligand‐induced Ca 2+ mobilization and membrane hyperpolarization, which is consistent with OT being more potent and efficacious at the human OTR. Specificity of the signaling at the OTR were confirmed using the vasopressin 1a receptor antagonist SR49059 and the oxytocin receptor antagonist L‐371,257. These data are consistent with previous reports that vasopressin 1a receptors are absent in SH‐SY5Y cells. Additionally, OT demonstrated a dose‐dependent increase in neurite outgrowth, which is inhibited by L‐371,257. Conclusions Together, these data demonstrate that OTR mediated signaling pathways lead to neurite outgrowth in SH‐SY5Y cells. Additional studies are needed to assess the specific molecular mechanisms that contribute to neurite outgrowth, and whether functional synapses are formed. Integrative studies of behavior, genetics and ligand‐receptor interaction are crucial for translating signaling activation at the cellular level to effects of AVP and OT ligands on social behavior. Knowledge of how OT alters neuronal structure and function has the potential to both identify mechanisms that produce social dysfunction and to inform the development of therapeutic agents.

The stimulatory action of centrally administered histamine (HA) on secretion of the anterior pituitary hormones ACTH, beta-endorphin, and PRL is indirect, and previous studies have suggested that hypothalamic neurons containing CRH, arginine vasopressin (AVP), and oxytocin (OT) are involved in this response. We studied the effect of HA on neuronal activation in the hypothalamus by investigating the expression of c-fos, which is a protooncogene activated early when neurons are stimulated. The expression of c-fos was evaluated by detection of c-fos immunoreactivity (c-fos-IR) using immunohistochemistry and by measurement of c-fos mRNA using in situ hybridization techniques. In addition, the identity of the HA-stimulated neurons was investigated by dual antigen immunohistochemistry visualizing AVP-, OT-, or CRH-IR in the neurons showing increased c-fos expression. HA (270 nmol) infused intracerebroventricularly increased c-fos-IR in the hypothalamus, especially in the periventricular hypothalamic areas and certain hypothalamic nuclei, including the paraventricular nucleus (PVN) and supraoptic nucleus (SON). c-fos-immunoreactive nuclei were observed throughout the SON, whereas in the PVN, c-fos-IR was particularly pronounced in the subnuclei known to contain AVP, OT, and CRH neurons. Double labeling experiments confirmed that c-fos was expressed in AVP-, OT-, and CRH-immunoreactive as well as other neurons. In addition, HA intracerebroventricularly induced a moderate expression of c-fos-IR in the arcuate nucleus. In situ hybridization showed increased levels of c-fos mRNA in both the PVN and SON after HA infusion. We conclude that HA-induced secretion of ACTH, beta-endorphin, and PRL may be mediated via activation of hypothalamic AVP, OT, and CRH neurons.

The stimulatory action of centrally administered histamine (HA) on secretion of the anterior pituitary hormones ACTH, beta-endorphin, and PRL is indirect, and previous studies have suggested that hypothalamic neurons containing CRH, arginine vasopressin (AVP), and oxytocin (OT) are involved in this response. We studied the effect of HA on neuronal activation in the hypothalamus by investigating the expression of c-fos, which is a protooncogene activated early when neurons are stimulated. The expression of c-fos was evaluated by detection of c-fos immunoreactivity (c-fos-IR) using immunohistochemistry and by measurement of c-fos mRNA using in situ hybridization techniques. In addition, the identity of the HA-stimulated neurons was investigated by dual antigen immunohistochemistry visualizing AVP-, OT-, or CRH-IR in the neurons showing increased c-fos expression. HA (270 nmol) infused intracerebroventricularly increased c-fos-IR in the hypothalamus, especially in the periventricular hypothalamic areas and certain hypothalamic nuclei, including the paraventricular nucleus (PVN) and supraoptic nucleus (SON). c-fos-immunoreactive nuclei were observed throughout the SON, whereas in the PVN, c-fos-IR was particularly pronounced in the subnuclei known to contain AVP, OT, and CRH neurons. Double labeling experiments confirmed that c-fos was expressed in AVP-, OT-, and CRH-immunoreactive as well as other neurons. In addition, HA intracerebroventricularly induced a moderate expression of c-fos-IR in the arcuate nucleus. In situ hybridization showed increased levels of c-fos mRNA in both the PVN and SON after HA infusion. We conclude that HA-induced secretion of ACTH, beta-endorphin, and PRL may be mediated via activation of hypothalamic AVP, OT, and CRH neurons.

Experiments were undertaken to test whether oxytocin (OT) may modulate the antipyretic action of arginine vasopressin (AVP) and to determine whether the action of endogenously released OT and/or AVP evoked by fever may modulate the motor actions of exogenous AVP. Intracerebroventricular (icv) injection of interleukin-1 alpha (IL-1 alpha, 40 ng) elicited a significantly attenuated rise in body temperature during the 2nd h of the febrile responses in OT-pretreated (0.1-10 pmol icv, 24 h earlier) rats. At the end of the 2nd h, administration of AVP (1 pmol icv), but not OT (10 pmol icv), significantly suppressed the febrile response in OT-pretreated but not in saline-pretreated rats. In nonfebrile OT-pretreated rats, 10 but not 1 pmol of AVP (icv) caused a significant decrease in body temperature. In rats pretreated with IL-1 alpha (40 ng icv) injection of AVP (100 pmol icv) induced enhanced motor responses. In summary, the ability of OT pretreatment to alter the febrile response to IL-1 alpha and the antipyretic action of AVP suggests a role for this peptide in fever. Furthermore, the observation that fever pretreatment can lower the threshold for convulsive-like behavior evoked by subsequent exposure to AVP raises the possibility that central OT and/or AVP released during fever could play a role in the genesis of febrile convulsions.