Vasopressin

NMDA Receptor in Vasopressin 1b Neurons Is Not Required for Short-Term Social Memory, Object Memory or Aggression.

Sarah K Williams Avram, Heon-Jin Lee, Jarrett Fastman +10 more

The arginine vasopressin 1b receptor (Avpr1b) plays an important role in social behaviors including aggression, social learning and memory. Genetic removal of Avpr1b from mouse models results in deficits in aggression and short-term social recognition in adults. Avpr1b gene expression is highly enriched in the pyramidal neurons of the hippocampal cornu ammonis 2 (CA2) region. Activity of the hippocampal CA2 has been shown to be required for normal short-term social recognition and aggressive behaviors. Vasopressin acts to enhance synaptic responses of CA2 neurons through a NMDA-receptor dependent mechanism. Genetic removal of the obligatory subunit of the NMDA receptor (Grin1) within distinct hippocampal regions impairs non-social learning and memory. However, the question of a direct role for NMDA receptor activity in Avpr1b neurons to modulate social behavior remains unclear. To answer this question, we first created a novel transgenic mouse line with Cre recombinase knocked into the Avpr1b coding region to genetically target Avpr1b neurons. We confirmed this line has dense Cre expression throughout the dorsal and ventral CA2 regions of the hippocampus, along with scattered expression within the caudate-putamen and olfactory bulb (OB). Conditional removal of the NMDA receptor was achieved by crossing our line to an available floxed Grin1 line. The resulting mice were measured on a battery of social and memory behavioral tests. Surprisingly, we did not observe any differences between Avpr1b-Grin1 knockout mice and their wildtype siblings. We conclude that mice without typical NMDA receptor function in Avpr1b neurons can develop normal aggression as well as short-term social and object memory performance.

Protective effect of pituitrin combined with norepinephrine on cardiopulmonary injury in patients with septic shock diagnosed by critical care ultrasound evaluation.

Henghao Cui, Xiaochun Yuan, Kai Lu +2 more

Septic shock is a life-threatening complication of sepsis, often accompanied by cardiopulmonary dysfunction, which significantly increases the mortality of patients. Norepinephrine (NE) is a commonly used vasopressor in the treatment of septic shock, but single-drug therapy may not fully achieve cardiopulmonary protection. Antidiuretic hormone (ADH) has potential regulatory effects on hemodynamics and inflammation, but its combined efficacy with NE in cardiopulmonary protection for septic patients remains to be further verified.

PVN AVP neurons projecting to MeA modulate social recognition and anxiety-like behavior in female mice.

Weizheng Zhang, Caihong Huang, Jing Liu +9 more

Arginine vasopressin (AVP) is well established in regulating social cognition and emotional responses in males. However, its roles in these processes in females and the underlying circuit mechanisms, remain poorly understood. In this study, female mice spent significantly more time sniffing the anogenital region of unfamiliar conspecifics compared to familiar individuals. Fiber photometry recordings revealed that the calcium activity in paraventricular nucleus of the hypothalamus (PVN) AVP neurons was elevated when sniffing unfamiliar mice relative to familiar ones. No significant differences were observed during non-social exploratory behaviors such as bedding sniffing or self-grooming, indicating a specific involvement of these neurons in social investigation. Retrograde tracing using cholera toxin B (CTB) confirmed direct projections from AVP neurons in the PVN to the medial amygdala (MeA). Chemogenetic inhibition of the PVN-MeA AVPergic pathway impaired social recognition and reduced anxiety-like behaviors. Furthermore, bilateral microinjection of the V1a receptor (V1aR) antagonist into the MeA decreased both anxiety-like behaviors and social investigation toward unfamiliar mice. These findings demonstrate that the AVPergic projection from the PVN to the MeA modulates social cognition and emotional state in female mice, providing a circuit mechanism for social and affective dysregulation and offering potential targets for the treatment of related neuropsychiatric disorders.

Intergenerational Postoperative Neurocognitive Disorder in a Rat Model: Initiating Mechanisms and Pharmacological Prevention.

Ling-Sha Ju, Zeeshan A Khan, Nikolaus Gravenstein +3 more

Vulnerability to perioperative neurocognitive disorder (PND) and the mechanisms initiating PND, which may serve as targets for prevention, are incompletely understood. This study hypothesized that sevoflurane can induce persistent upregulation of the hypothalamic-pituitary-adrenal axis, inflammation, and behavioral deficits in young adult male rats by stimulating hypothalamic arginine vasopressin (AVP) production via Na + -K + -Cl - (NKCC1) Cl - importer/γ-aminobutyric acid type A receptor signaling. These changes may also result in neurocognitive deficits in the offspring of exposed rats ( i.e. , intergenerational PND).

Vasopressin and its analogues in patients with septic shock: holy Grail or unfulfilled promise?

Quentin Lajoye, Arthur Orieux, Alexandre Boyer +2 more

The Surviving Sepsis Campaign (SSC) recommends norepinephrine as first-line vasopressor in patients with septic shock. For many years, there has been growing evidence that high doses of norepinephrine might have cardiac and immunological adverse effects and be associated with poorer outcomes. Current SSC guidelines therefore suggest adding vasopressin, a non-catecholaminergic vasopressor, as a second-line vasopressor rather than increasing the norepinephrine dose in patients requiring doses of norepinephrine base > 0.25-0.50 µg/kg/min, after excluding persistent hypovolemia and cardiac dysfunction. Vasopressin is a peptide hormone that causes vasoconstriction through its specific receptor, the arginine vasopressin receptor V1. Up to one-third of patients with septic shock may have vasopressin deficiency, which contributes to refractory septic shock. Vasopressin use is associated with a norepinephrine-sparing effect, which may in turn reduce the complications induced by high-doses of norepinephrine, by decreasing the vasopressor load: this is the concept of decatecholaminization. Nevertheless, the use of vasopressin in patients with septic shock has not yet demonstrated clear benefits in terms of patient outcomes, such as less cardiotoxicity, reduced use of renal replacement therapy or decreased mortality. The heterogeneity in the use of vasopressin and the definition of early vasopressin administration between different studies as well as many unresolved issues regarding the use of vasopressin in patients with septic shock could explain the absence of clear and relevant clinical benefits. Thus, the identification of subgroups of patients likely to benefit the most from vasopressin, the management of vasopressin administration (time to initiation, optimal doses, weaning strategy) and a better understanding of the interactions between vasopressin and corticosteroids represent major areas of research for future studies.

Nebulized vasopressin penetrates CSF and improves social cognition without inducing aggression in a rhesus monkey model of autism.

Catherine F Talbot, Ozge Oztan, Sierra M V Simmons +7 more

Low cerebrospinal (CSF) arginine vasopressin (AVP) concentration is a biomarker of social impairment in low-social monkeys and children with autism, suggesting that AVP administration may improve primate social functioning. However, AVP administration also increases aggression, at least in "neurotypical" animals with intact AVP signaling. Here, we tested the effects of a voluntary drug administration method in low-social male rhesus monkeys with high autistic-like trait burden. Monkeys received nebulized AVP or placebo, using a within-subjects design. Study 1 (N = 8) investigated the effects of AVP administration on social cognition in two tests comparing responses to social versus nonsocial stimuli. Test 1: Placebo-administered monkeys lacked face recognition memory, whereas face recognition memory was "rescued" following AVP administration. In contrast, object recognition memory was intact and did not differ between administration conditions. Test 2: Placebo-administered monkeys did not respond to conspecific social communication cues, whereas following AVP administration, they reciprocated affiliative communication cues with species-typical affiliative responses. Importantly, AVP administration did not increase aggressive responses to conspecific aggressive or affiliative overtures. Study 2 (N = 4) evaluated the pharmacokinetics of this administration method. Following AVP nebulization, we observed a linear increase in cisternal CSF AVP levels, and a quadratic rise and fall in blood AVP levels. These findings indicate that nebulized AVP likely penetrates the central nervous system, selectively promotes species-typical responses to social information, and does not induce aggression in low-social individuals. Nebulized AVP therefore may hold promise for managing similar social symptoms in people with autism, particularly in very young or lower functioning individuals.

A Novel Early Life Stress Model Affects Brain Development and Behavior in Mice.

Hyun Seung Shin, Soo Min Choi, Seung Hyun Lee +2 more

Early life stress (ELS) in developing children has been linked to physical and psychological sequelae in adulthood. In the present study, we investigated the effects of ELS on brain and behavioral development by establishing a novel ELS model that combined the maternal separation paradigm and mesh platform condition. We found that the novel ELS model caused anxiety- and depression-like behaviors and induced social deficits and memory impairment in the offspring of mice. In particular, the novel ELS model induced more enhanced depression-like behavior and memory impairment than the maternal separation model, which is the established ELS model. Furthermore, the novel ELS caused upregulation of arginine vasopressin expression and downregulation of GABAergic interneuron markers, such as parvalbumin (PV), vasoactive intestinal peptide, and calbindin-D28k (CaBP-28k), in the brains of the mice. Finally, the offspring in the novel ELS model showed a decreased number of cortical PV-, CaBP-28k-positive cells and an increased number of cortical ionized calcium-binding adaptors-positive cells in their brains compared to mice in the established ELS model. Collectively, these results indicated that the novel ELS model induced more negative effects on brain and behavioral development than the established ELS model.

Sudden Vasopressin Withdrawal Causing Transient Central Diabetes Insipidus: A Case Report.

Ramakanth Pata, Nway Nway, Ilana K Logvinsky +2 more

Vasopressin is a peptide hormone produced by the hypothalamus and stored in the posterior pituitary. It is secreted in response to hypotension and hyperosmolarity. Vasopressin and its analogs have been widely used in vasodilatory shocks such as septic shock and cardiogenic shock. The sudden withdrawal of vasopressin after its prolonged use can lead to polyuria and rising sodium levels, which is concerning for the diagnosis of diabetic insipidus (DI); likely central rather than nephrogenic in origin. We present a case of diabetic insipidus following the sudden discontinuation of a prolonged vasopressin infusion for septic shock, which responded to tapering doses of desmopressin.

Oxytocin and Related Peptide Hormones: Candidate Anti-Inflammatory Therapy in Early Stages of Sepsis.

Syed Faizan Mehdi, Suma Pusapati, Raja Ram Khenhrani +10 more

Sepsis is a potentially life-threatening systemic inflammatory syndrome characterized by dysregulated host immunological responses to infection. Uncontrolled immune cell activation and exponential elevation in circulating cytokines can lead to sepsis, septic shock, multiple organ dysfunction syndrome, and death. Sepsis is associated with high re-hospitalization and recovery may be incomplete, with long term sequelae including post-sepsis syndrome. Consequently, sepsis continues to be a leading cause of morbidity and mortality across the world. In our recent review of human chorionic gonadotropin (hCG), we noted that its major properties including promotion of fertility, parturition, and lactation were described over a century ago. By contrast, the anti-inflammatory properties of this hormone have been recognized only more recently. Vasopressin, a hormone best known for its anti-diuretic effect, also has anti-inflammatory actions. Surprisingly, vasopressin's close cousin, oxytocin, has broader and more potent anti-inflammatory effects than vasopressin and a larger number of pre-clinical studies supporting its potential role in limiting sepsis-associated organ damage. This review explores possible links between oxytocin and related octapeptide hormones and sepsis-related modulation of pro-inflammatory and anti-inflammatory activities.

Neural correlates of mating system diversity: oxytocin and vasopressin receptor distributions in monogamous and non-monogamous Eulemur.

Nicholas M Grebe, Annika Sharma, Sara M Freeman +4 more

Contemporary theory that emphasizes the roles of oxytocin and vasopressin in mammalian sociality has been shaped by seminal vole research that revealed interspecific variation in neuroendocrine circuitry by mating system. However, substantial challenges exist in interpreting and translating these rodent findings to other mammalian groups, including humans, making research on nonhuman primates crucial. Both monogamous and non-monogamous species exist within Eulemur, a genus of strepsirrhine primate, offering a rare opportunity to broaden a comparative perspective on oxytocin and vasopressin neurocircuitry with increased evolutionary relevance to humans. We performed oxytocin and arginine vasopressin 1a receptor autoradiography on 12 Eulemur brains from seven closely related species to (1) characterize receptor distributions across the genus, and (2) examine differences between monogamous and non-monogamous species in regions part of putative "pair-bonding circuits". We find some binding patterns across Eulemur reminiscent of olfactory-guided rodents, but others congruent with more visually oriented anthropoids, consistent with lemurs occupying an 'intermediary' evolutionary niche between haplorhine primates and other mammalian groups. We find little evidence of a "pair-bonding circuit" in Eulemur akin to those proposed in previous rodent or primate research. Mapping neuropeptide receptors in these nontraditional species questions existing assumptions and informs proposed evolutionary explanations about the biological bases of monogamy.

Arginine vasopressin receptor 2 activation promotes microvascular permeability in sepsis.

Ernesto Lopez, Satoshi Fukuda, Katalin Modis +9 more

Methicillin-resistant Staphylococcus aureus (MRSA) sepsis is a severe condition associated with vascular leakage and poor prognosis. The hemodynamic management of sepsis targets hypotension, but there is no specific treatment available for vascular leakage. Arginine vasopressin (AVP) has been used in sepsis to promote vasoconstriction by activating AVP receptor 1 (V1R). However, recent evidence suggests that increased fluid retention may be associated with the AVP receptor 2 (V2R) activation worsening the outcome of sepsis. Hence, we hypothesized that the inhibition of V2R activation ameliorates the severity of microvascular hyperpermeability during sepsis. The hypothesis was tested using a well-characterized and clinically relevant ovine model of MRSA pneumonia/sepsis and in vitro assays of human lung microvascular endothelial cells (HMVECs). in vivo experiments demonstrated that the treatment of septic sheep with tolvaptan (TLVP), an FDA-approved V2R antagonist, significantly attenuated the sepsis-induced fluid retention and markedly reduced the lung water content. These pathological changes were not affected by the treatment with V2R agonist, desmopressin (DDAVP). Additionally, the incubation of cultured HMVECs with DDAVP, and DDAVP along with MRSA significantly increased the paracellular permeability. Finally, both the DDAVP and MRSA-induced hyperpermeability was significantly attenuated by TLVP. Subsequent protein and gene expression assays determined that the V2R-induced increase in permeability is mediated by phospholipase C beta (PLCβ) and the potent permeability factor angiopoietin-2. In conclusion, our results indicate that the activation of the AVP-V2R axis is critical in the pathophysiology of severe microvascular hyperpermeability during Gram-positive sepsis. The use of the antagonist TLVP should be considered as adjuvant treatment for septic patients. The results from this clinically relevant animal study are highly translational to clinical practice.

Sex differences of oxytocin and vasopressin in social behaviors.

Qiaoqiao Lu, Shaohua Hu

The neuropeptides oxytocin (OT) and vasopressin (VP) are known to mediate social cognition and behaviors in a sex-dependent manner. This chapter reviews the sex-dependent influence of OT and VP on social behaviors, focusing on (1) partner preference and sexual orientation, (2) memory modulation, (3) emotion regulation, and (4) trust-related behaviors. Most studies suggest that OT promotes familiar (opposite-sex) partner preference, strengthens memory, relieves anxiety, and increases trust. However, VP-regulated social cognition has been studied less than OT. VP facilitates familiar (opposite-sex) partner preference, enhances memory, induces anxiety, and influences happiness/anger perception. Detailed sex differences of these effects are reviewed. There is a male preponderance in the use of animal models and many study results are too complex to draw firm conclusions. Clarifying the complex interplay between the OT/VP system and sex hormones in the regulation of social behaviors is needed.

The role of oxytocin and vasopressin dysfunction in cognitive impairment and mental disorders.

Olga Abramova, Yana Zorkina, Valeria Ushakova +3 more

Oxytocin (OXT) and arginine-vasopressin (AVP) are structurally homologous peptide hormones synthesized in the hypothalamus. Nowadays, the role of OXT and AVP in the regulation of social behaviour and emotions is generally known. However, recent researches indicate that peptides also participate in cognitive functioning. This review presents the evidence that the OXT/AVP systems are involved in the formation of social, working, spatial and episodic memory, mediated by such brain structures as the hippocampal CA2 and CA3 regions, amygdala and prefrontal cortex. Some data have demonstrated that the OXT receptor's polymorphisms are associated with impaired memory in humans, and OXT knockout in mice is connected with memory deficit. Additionally, OXT and AVP are involved in mental disorders' progression. Stress-induced imbalance of the OXT/AVP systems leads to an increased risk of various mental disorders, including depression, schizophrenia, and autism. At the same time, cognitive deficits are observed in stress and mental disorders, and perhaps peptide hormones play a part in this. The final part of the review describes possible therapeutic strategies for the use of OXT and AVP for treatment of various mental disorders.

Vasopressin Administration Is Associated With Rising Serum Lactate Levels in Patients With Sepsis.

Kristen A Severson, Laura Ritter-Cox, Jesse D Raffa +2 more

Vasopressin is used in conjunction with norepinephrine during treatment of patients with septic shock. Serum lactate is often used in monitoring of patients with sepsis; however, its importance as a therapeutic target is unclear. The objective of this study is to examine the relationship of vasopressin use on serum lactate levels in patients with sepsis.

Vasopressin and post-traumatic stress disorder.

Eszter Sipos, Bibiána Török, István Barna +2 more

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition with a wide range of behavioral disturbances and serious consequences for both patient and society. One of the main reasons for unsuccessful therapies is insufficient knowledge about its underlying pathomechanism. In the search for centrally signaling molecules that might be relevant to the development of PTSD we focus here on arginine vasopressin (AVP). So far AVP has not been strongly implicated in PTSD, but different lines of evidence suggest a possible impact of its signaling in all clusters of PTSD symptomatology. More specifically, in laboratory rodents, AVP agonists affect behavior in a PTSD-like manner, while significant reduction of AVP signaling in the brain e.g. in AVP-deficient Brattleboro rats, ameliorated defined behavioral parameters that can be linked to PTSD symptoms. Different animal models of PTSD also show alterations in the AVP signaling in distinct brain areas. However, pharmacological treatment targeting central AVP receptors via systemic routes is hampered by possible side effects that are linked to the peripheral action of AVP as a hormone. Indeed, the V1a receptor, the most common receptor subtype in the brain, is implicated in vasoconstriction. Thus, systemic treatment with V1a receptor antagonists would be implicated in hypotonia. This implies that novel treatment concepts are needed to target AVP receptors not only at brain level but also in distinct brain areas, to offer alternative treatments for PTSD.

Altered Behaviors and Impaired Synaptic Function in a Novel Rat Model With a Complete Shank3 Deletion.

Tian-Jia Song, Xing-Yu Lan, Meng-Ping Wei +15 more

Mutations within the Shank3 gene, which encodes a key postsynaptic density (PSD) protein at glutamatergic synapses, contribute to the genetic etiology of defined autism spectrum disorders (ASDs), including Phelan-McDermid syndrome (PMS) and intellectual disabilities (ID). Although there are a series of genetic mouse models to study Shank3 gene in ASDs, there are few rat models with species-specific advantages. In this study, we established and characterized a novel rat model with a deletion spanning exons 11-21 of Shank3, leading to a complete loss of the major SHANK3 isoforms. Synaptic function and plasticity of Shank3-deficient rats were impaired detected by biochemical and electrophysiological analyses. Shank3-depleted rats showed impaired social memory but not impaired social interaction behaviors. In addition, impaired learning and memory, increased anxiety-like behavior, increased mechanical pain threshold and decreased thermal sensation were observed in Shank3-deficient rats. It is worth to note that Shank3-deficient rats had nearly normal levels of the endogenous social neurohormones oxytocin (OXT) and arginine-vasopressin (AVP). This new rat model will help to further investigate the etiology and assess potential therapeutic target and strategy for Shank3-related neurodevelopmental disorders.

Social Context, Stress, Neuropsychiatric Disorders, and the Vasopressin 1b Receptor.

Heather K Caldwell, Elizabeth A Aulino, Karla M Rodriguez +2 more

The arginine vasopressin 1b receptor (Avpr1b) is involved in the modulation of a variety of behaviors and is an important part of the mammalian hormonal stress axis. The Avpr1b is prominent in hippocampal CA2 pyramidal cells and in the anterior pituitary corticotrophs. Decades of research on this receptor has demonstrated its importance to the modulation of social recognition memory, social forms of aggression, and modulation of the hypothalamic-pituitary-adrenal axis, particularly under conditions of acute stress. Further, work in humans suggests that the Avpr1b may play a role in human neuropsychiatric disorders and its modulation may have therapeutic potential. This paper reviews what is known about the role of the Avpr1b in the context of social behaviors, the stress axis, and human neuropsychiatric disorders. Further, possible mechanisms for how Avpr1b activation within the hippocampus vs. Avpr1b activation within anterior pituitary may interact with one another to affect behavioral output are proposed.

Post-weaning social isolation exacerbates aggression in both sexes and affects the vasopressin and oxytocin system in a sex-specific manner.

Vinícius Elias de Moura Oliveira, Inga D Neumann, Trynke R de Jong

Post-weaning social isolation (PWSI) is known to induce exaggerated and abnormal aggression in male rats. Here we aimed to assess the effects of PWSI on aggressiveness and social behavior in both male and female rats. Furthermore, we evaluated how PWSI affects the central oxytocin (OXT) and vasopressin (AVP) systems in both sexes. Wistar rats were isolated (IS) or group housed (GH) in same-sex groups immediately after weaning. After seven weeks, rats underwent an intruder test to assess aggression. In one group, brains were immediately dissected afterwards for in situ hybridization and receptor autoradiography. The other group underwent additional anxiety-like and social behavior tests. PWSI induced increased (abnormal) aggression and impaired social memory in both sexes. Especially IS females exhibited abnormal aggression towards juveniles. Furthermore, PWSI increased OXT mRNA expression in the paraventricular nucleus of the hypothalamus (PVN) and decreased OXTR binding in the anterior portion of the nucleus accumbens (NAcc), independent of the sex. V1a receptor binding was decreased in the lateral hypothalamus (LH) and dentate gyrus (DG) in IS rats, regardless of sex. However, V1a receptor binding in the anterior portion of the bed nucleus of stria terminalis (BNSTa) was decreased in IS females but increased in IS males. Taken together, our data support PWSI as a reliable model to exacerbate aggression not only in male but also in female rats. In addition, OXT receptors in the NAcca and V1a receptors in the LH, DG, and BNSTa may play a role in the link between PWSI and aggression. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.

A circuit from hippocampal CA2 to lateral septum disinhibits social aggression.

Felix Leroy, Jung Park, Arun Asok +6 more

Although the hippocampus is known to be important for declarative memory, it is less clear how hippocampal output regulates motivated behaviours, such as social aggression. Here we report that pyramidal neurons in the CA2 region of the hippocampus, which are important for social memory, promote social aggression in mice. This action depends on output from CA2 to the lateral septum, which is selectively enhanced immediately before an attack. Activation of the lateral septum by CA2 recruits a circuit that disinhibits a subnucleus of the ventromedial hypothalamus that is known to trigger attack. The social hormone arginine vasopressin enhances social aggression by acting on arginine vasopressin 1b receptors on CA2 presynaptic terminals in the lateral septum to facilitate excitatory synaptic transmission. In this manner, release of arginine vasopressin in the lateral septum, driven by an animal's internal state, may serve as a modulatory control that determines whether CA2 activity leads to declarative memory of a social encounter and/or promotes motivated social aggression.

Vasopressin in Vasodilatory Shock.

Ida-Fong Ukor, Keith R Walley

Vasodilatory shock is the final common pathway for all forms of severe shock, with sepsis the most common primary etiology and the leading cause of critical illness-related mortality. The pathophysiology of this condition remains incompletely elucidated. Deficiency of the neuropeptide hormone vasopressin seems to play a significant role. The physiology of vasopressin and its interaction with the pathophysiology of vasodilatory shock are described in this review. A brief review of the major randomized controlled trials assessing the efficacy and safety of vasopressin and its analogs in this complex patient cohort is also provided.

Targeted activation of the hippocampal CA2 area strongly enhances social memory.

A S Smith, S K Williams Avram, A Cymerblit-Sabba +2 more

Social cognition enables individuals to understand others' intentions. Social memory is a necessary component of this process, for without it, subsequent encounters are devoid of any historical information. The CA2 area of the hippocampus, particularly the vasopressin 1b receptor (Avpr1b) expressed there, is necessary for memory formation. We used optogenetics to excite vasopressin terminals, originating from the hypothalamic paraventricular nucleus, in the CA2 of mice. This markedly enhanced their social memory if the stimulation occurred during memory acquisition, but not retrieval. This effect was blocked by an Avpr1b antagonist. Finally, this enhanced memory is resistant to the social distraction of an introduced second mouse, important for socially navigating populations of individuals. Our results indicate the CA2 can increase the salience of social signals. Targeted pharmacotherapy with Avpr1b agonists or deep brain stimulation of the CA2 are potential avenues of treatment for those with declining social memory as in various dementias.

Oxytocin (OT) and arginine-vasopressin (AVP) act on OT receptors and not AVP V1a receptors to enhance social recognition in adult Syrian hamsters (Mesocricetus auratus).

Zhimin Song, Tony E Larkin, Maureen O' Malley +1 more

Social recognition is a fundamental requirement for all forms of social relationships. A majority of studies investigating the neural mechanisms underlying social recognition in rodents have investigated relatively neutral social stimuli such as juveniles or ovariectomized females over short time intervals (e.g., 2h). The present study developed a new testing model to study social recognition among adult males using a potent social stimulus. Flank gland odors are used extensively in social communication in Syrian hamsters and convey important information such as dominance status. We found that the recognition of flank gland odors after a 3min exposure lasted for at least 24h, substantially longer than the recognition of other social cues in rats and mice. Intracerebroventricular injections of OT and AVP prolonged the recognition of flank gland odor for up to 48h. Selective OTR but not V1aR agonists, mimicked these enhancing effects of OT and AVP. Similarly, selective OTR but not V1aR antagonists blocked recognition of the odors after 20min. In contrast, the recognition of non-social stimuli was not blocked by either the OTR or the V1aR antagonists. Our findings suggest both OT and AVP enhance social recognition via acting on OTRs and not V1aRs and that the recognition enhancing effects of OT and AVP are limited to social stimuli.

Genotypic differences in intruder-evoked immediate early gene activation in male, but not female, vasopressin 1b receptor knockout mice.

Shannah K Witchey, Erica L Stevenson, Heather K Caldwell

The neuropeptide arginine vasopressin (Avp) modulates social behaviors via its two centrally expressed receptors, the Avp 1a receptor and the Avp 1b receptor (Avpr1b). Recent work suggests that, at least in mice, Avp signaling through Avpr1b within the CA2 region of the hippocampus is critical for normal aggressive behaviors and social recognition memory. However, this brain area is just one part of a larger neural circuit that is likely to be impacted in Avpr1b knockout (-/-) mice. To identify other brain areas that are affected by altered Avpr1b signaling, genotypic differences in immediate early gene activation, i.e. c-FOS and early growth response factor 1 (EGR-1), were quantified using immunocytochemistry following a single exposure to an intruder.

Possible contribution of epigenetic changes in the development of schizophrenia-like behavior in vasopressin-deficient Brattleboro rats.

Kornél Demeter, Bibiána Török, Anna Fodor +6 more

Schizophrenia-like symptoms were detected in vasopressin-deficient (di/di) Brattleboro rats, and it was also suggested that schizophrenia might have an epigenetic component. We aimed to clarify if epigenetic changes contribute to schizophrenia-like behavior of this strain. Behavioral (locomotion by telemetry, cognition by novel object recognition, social recognition and social avoidance test, attention by pre-pulse inhibition) and epigenetic differences were compared between wild type and di/di animals. DNA methyltransferase1 (DNMT1), DNMT3a, as well as COMT, GAD, VGLUT1, 5HT2A, BDNF mRNA levels in prefrontal brain region and hippocampus were studied by qRT-PCR. Histone3 (H3) and H4 acetylation (Ac) were studied by western-blot followed by region specific examination of H3 lysine9 (K9) acetylation by immunohistochemistry. Impaired cognitive, social and attention behavior of di/di rats confirmed schizophrenia-like symptoms in our local colony. The pan-AcH3 immunoreactivity was lower in prefrontal region and elevated in the hippocampus of di/di animals. We found lower immunopositive cell number in the dorsal peduncular prefrontal cortex and the ventral lateral septum and increased AcH3K9 immunoreactivity in CA1 region of di/di animals. There were no major significant alterations in the studied mRNA levels. We confirmed that Brattleboro rat is a good preclinical model of schizophrenia. Its schizophrenia-like behavioral alteration was accompanied by changes in H3 acetylation in the prefrontal region and hippocampus. This may contribute to disturbances of many schizophrenia-related substances leading to development of schizophrenia-like symptoms. Our studies confirmed that not a single gene, rather fine changes in an array of molecules are responsible for the majority of schizophrenia cases.

Exogenous Vasopressin-Induced Hyponatremia in Patients With Vasodilatory Shock: Two Case Reports and Literature Review.

Miguel Salazar, Bee Bee Hu, Joyce Vazquez +2 more

Vasopressin has gained wide support as an adjunct vasopressor in patients with septic shock. This agent exerts its vasoconstriction effects through smooth muscle V1 receptors and also has antidiuretic activity via renal V2 receptors. This interaction with the renal V2 receptors results in the integration of aquaporin 2 channels in the apical membrane of the renal collecting duct leading to free water reabsorption. Thus, water intoxication with subsequent hyponatremia, although rare, is a potentially serious side effect of exogenous vasopressin administration. We present 2 patients who developed hyponatremia within hours of initiation of vasopressin infusion. Extensive diuresis followed its discontinuation with subsequent normalization of serum sodium. One of the patients required the use of hypertonic saline for more rapid normalization of serum sodium due to concerns for potential seizure activity. A review of the literature relevant to the incidence of vasopressin-induced hyponatremia is provided as well as discussion on additional factors relevant to septic shock that should be considered when determining the relative risk of hyponatremia in patients receiving vasopressin.

Sevoflurane-induced down-regulation of hippocampal oxytocin and arginine vasopressin impairs juvenile social behavioral abilities.

Zhi-Bin Zhou, Xiao-Yu Yang, Bao-Long Yuan +5 more

Cumulative evidence indicates that early childhood anesthesia can alter a child's future behavioral performance. Animal researchers have found that sevoflurane, the most commonly used anesthetic for children, can produce damage in the neonatal brains of rodents. To further investigate this phenomenon, we focused on the influence of sevoflurane anesthesia on the development of juvenile social behavioral abilities and the pro-social proteins oxytocin (OT) and arginine vasopressin (AVP) in the neonatal hippocampus. A single 6-h sevoflurane exposure for postnatal day 5 mice resulted in decreased OT and AVP messenger RNA (mRNA) and protein levels in the hippocampus. OT and AVP proteins became sparsely distributed in the dorsal hippocampus after the exposure to sevoflurane. Compared with the air-treated group, mice in the sevoflurane-treated group showed signs of impairment in social recognition memory formation and social discrimination ability. Sevoflurane anesthesia reduces OT and AVP activities in the neonatal hippocampus and impairs social recognition memory formation and social discrimination ability in juvenile mice.

Introduction of the human AVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic mice.

Rhonda Charles, Takeshi Sakurai, Nagahide Takahashi +4 more

Central arginine vasopressin receptor 1A (AVPR1A) modulates a wide range of behaviors, including stress management and territorial aggression, as well as social bonding and recognition. Inter- and intra-species variations in the expression pattern of AVPR1A in the brain and downstream differential behavioral phenotypes have been attributed to differences in the non-coding regions of the AVPR1A gene, including polymorphic elements within upstream regulatory areas. Gene association studies have suggested a link between AVPR1A polymorphisms and autism, and AVPR1A has emerged as a potential pharmacological target for treatment of social cognitive impairments and mood and anxiety disorders. To further investigate the genetic mechanism giving rise to species differences in AVPR1A expression patterns and associated social behaviors, and to create a preclinical mouse model useful for screening drugs targeting AVPR1A, we engineered and extensively characterized bacterial artificial chromosome (BAC) transgenic mice harboring the entire human AVPR1A locus with the surrounding regulatory elements. Compared with wild-type animals, the humanized mice displayed a more widely distributed ligand-AVPR1A binding pattern, which overlapped with that of primates. Furthermore, humanized AVPR1A mice displayed increased reciprocal social interactions compared with wild-type animals, but no differences in social approach and preference for social novelty were observed. Aspects of learning and memory, specifically novel object recognition and spatial relocation recognition, were unaffected. The biological alterations in humanized AVPR1A mice resulted in the rescue of the prepulse inhibition impairments that were observed in knockout mice, indicating conserved functionality. Although further behavioral paradigms and additional cohorts need to be examined in humanized AVPR1A mice, the results demonstrate that species-specific variations in the genomic content of regulatory regions surrounding the AVPR1A locus are responsible for differential receptor protein expression patterns across species and that they are likely to contribute to species-specific behavioral variation. The humanized AVPR1A mouse is a potential preclinical model for further understanding the regulation of receptor gene expression and the impact of variation in receptor expression on behaviors, and should be useful for screening drugs targeting human AVPR1A, taking advantage of the expression of human AVPR1A in human-relevant brain regions.

Oxytocin in learning and addiction: From early discoveries to the present.

Zoltán Sarnyai, Gábor L Kovács

Oxytocin (OXT) has a plethora of effects on brain function. This review provides a historical overview of the development of research on OXT and drug addiction. By focusing on research that has emerged from our laboratories, we describe how early discoveries of the influence of OXT on learning and memory processes and the emerging conceptualization of addiction as 'pathological learning' have contributed to the demonstration that OXT effectively attenuates long-term neuroadaptation related to opiate and psychostimulant addiction. Through integrating earlier evidence with recent discoveries of the social/affiliative role of OXT, we propose that OXT may interfere with reward and addiction by influencing neurobiological processes involved in stress, learning and memory and social/affiliative behavior.

Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction.

James K Rilling, Ashley C DeMarco, Patrick D Hackett +8 more

Both oxytocin (OT) and vasopressin (AVP) are known to modulate social behavior, and dysfunction in both systems has been postulated as a potential cause of certain psychiatric disorders that involve social behavioral deficits. In particular, there is growing interest in intranasal OT as a potential treatment for certain psychiatric disorders, and preliminary pre-clinical and clinical studies suggest efficacy in alleviating some of the associated symptoms. However, the vast majority of research participants in these studies have been male, and there is evidence for sexually differentiated effects of nonapeptides in both humans and non-human animals. To date, no study has investigated the effect of intranasal OT on brain function in human males and females within the same paradigm. Previously, in a randomized, placebo-controlled, double-blind fMRI study, we reported effects of intranasal OT and AVP on behavior and brain activity of human males as they played an interactive social game known as the Prisoner's Dilemma Game. Here, we present findings from an identical study in human females, and compare these with our findings from males. Overall, we find that both behavioral and neural responses to intranasal OT and AVP are highly sexually differentiated. In women, AVP increased conciliatory behavior, and both OT and AVP caused women to treat computer partners more like humans. In men, AVP increased reciprocation of cooperation from both human and computer partners. However, no specific drug effects on behavior were shared between men and women. During cooperative interactions, both OT and AVP increased brain activity in men within areas rich in OT and AVP receptors and in areas playing a key role in reward, social bonding, arousal and memory (e.g., the striatum, basal forebrain, insula, amygdala and hippocampus), whereas OT and AVP either had no effect or in some cases actually decreased brain activity in these regions in women. OT treatment rendered neural responses of males more similar to responses of females in the placebo group and vice versa, raising the prospect of an inverted u-shaped dose response to central OT levels. These findings emphasize the need to fully characterize the effects of intranasal OT and AVP in both males and females and at multiple doses before widespread clinical application will be warranted.

The role of oxytocin in plasticity, memory and attachment dynamics.

F Orsucci, G Paoloni, C M Conti +2 more

The peptide hormones oxytocin (OT) and arginine vasopressin (AVP) have been implicated in the regulation of mammalian social behavior. There is considerable evidence implicating both oxytocin and vasopressin in social recognition and social memory. This review explores their role in attachment dynamics. Oxytocin is one element in a complex network of interactions observed in natural phenomena ranging from molecular biology, etology, social behavior and human psychology.