Maternal aggression in rodents: brain oxytocin and vasopressin mediate pup defence

The most significant social behaviour of the lactating mother is maternal behaviour, which comprises maternal care and maternal aggression (MA). The latter is a protective behaviour of the mother serving to defend the offspring against a potentially dangerous intruder. The extent to which the mother shows aggressive behaviour depends on extrinsic and intrinsic factors, as we have learned from studies in laboratory rodents. Among the extrinsic factors are the pups’ presence and age, as well as the intruders’ sex and age. With respect to intrinsic factors, the mothers’ innate anxiety and the prosocial brain neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) play important roles. While OXT is well known as a maternal neuropeptide, AVP has only recently been described in this context. The increased activities of these neuropeptides in lactation are the result of remarkable brain adaptations peripartum and are a prerequisite for the mother to become maternal. Consequently, OXT and AVP are significantly involved in mediating the fine-tuned regulation of MA depending on the brain regions. Importantly, both neuropeptides are also modulators of anxiety, which determines the extent of MA. This review provides a detailed overview of the role of OXT and AVP in MA and the link to anxiety.     

The contributions of oxytocin and vasopressin pathway genes to human behavior

Arginine vasopressin (AVP) and oxytocin (OXT) are social hormones and mediate affiliative behaviors in mammals and as recently demonstrated, also in humans. There is intense interest in how these simple nonapeptides mediate normal and abnormal behavior, especially regarding disorders of the social brain such as autism that are characterized by deficits in social communication and social skills. The current review examines in detail the behavioral genetics of the first level of human AVP-OXT pathway genes including arginine vasopressin 1a receptor (AVPR1a), oxytocin receptor (OXTR), AVP (AVP-neurophysin II [NPII]) and OXT (OXT neurophysin I [NPI]), oxytocinase/vasopressinase (LNPEP), ADP-ribosyl cyclase (CD38) and arginine vasopressin 1b receptor (AVPR1b). Wherever possible we discuss evidence from a variety of research tracks including molecular genetics, imaging genomics, pharmacology and endocrinology that support the conclusions drawn from association studies of social phenotypes and detail how common polymorphisms in AVP-OXT pathway genes contribute to the behavioral hard wiring that enables individual Homo sapiens to interact successfully with conspecifics. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.     

AVPR1b variation and the emergence of adaptive phenotypes in Platyrrhini primates

Platyrrhini (New World monkeys, NWm) are a group of primates characterized by behavioral and reproductive traits that are otherwise uncommon among primates, including social monogamy, direct paternal care, and twin births. As a consequence, the study of Platyrrhine primates is an invaluable tool for the discovery of the genetic repertoire underlying these taxon‐specific traits. Recently, high conservation of vasopressin (AVP) sequence, in contrast with high variability of oxytocin (OXT), has been described in NWm. AVP and OXT functions are possible due to interaction with their receptors: AVPR1a, AVPR1b, AVPR2, and OXTR; and the variability in this system is associated with the traits mentioned above. Understanding the variability in the receptors is thus fundamental to understand the function and evolution of the system as a whole. Here we describe the variability of AVPR1b coding region in 20 NWm species, which is well‐known to influence behavioral traits such as aggression, anxiety, and stress control in placental mammals. Our results indicate that 4% of AVPR1b sites may be under positive selection and a significant number of sites under relaxed selective constraint. Considering the known role of AVPR1b, we suggest that some of the changes described here for the Platyrrhini may be a part of the genetic repertoire connected with the complex network of neuroendocrine mechanisms of AVP–OXT system in the modulation of the HPA axis. Thus, these changes may have promoted the emergence of social behaviors such as direct paternal care in socially monogamous species that are also characterized by small body size and twin births.     

Oxytocin, but not arginine vasopressin is involving in the antinociceptive role of hypothalamic supraoptic nucleus

Our pervious study has demonstrated that the hypothalamic supraoptic nucleus (SON) plays a role in pain modulation. Oxytocin (OXT) and arginine vasopressin (AVP) are the important hormones synthesized and secreted by the SON. The experiment was designed to investigate which hormone was relating with the antinociceptive role of the SON in the rat. The results showed that (1) microinjection of l-glutamate sodium into the SON increased OXT and AVP concentrations in the SON perfusion liquid, (2) pain stimulation induces OXT, but not AVP release in the SON, and (3) intraventricular injection (pre-treatment) with OXT antiserum could inhibit the pain threshold increase induced by SON injection of l-glutamate sodium, but administration of AVP antiserum did not influence the antinociceptive role of SON stimulation. The data suggested that the antinociceptive role of the SON relates to OXT rather than AVP.     

Tyrosinate fluorescence lifetimes for oxytocin and vasopressin in receptor-simulating environments: relationship to biological activity and 1H-NMR data

Nanosecond time-resolved tyrosinate fluorescence lifetimes were compared for oxytocin (OXT) and vasopressin (AVP) in propylene glycol. Long-lifetime tyrosinate fluorescence (LTF), characteristic of stable intramolecular hydrogen bond formation of the Tyr hydroxyl group, was present for OXT but not AVP in propylene glycol. The Tyr OH proton was also found to be labile for OXT but not AVP in DMSO by 1H-NMR. The spectroscopic data illustrate that the Tyr hydroxyl in OXT participates in an intramolecular hydrogen bond in certain receptor-simulating environments; the absence of potent LTF for [Ala5] OXT suggests that the Tyr hydroxyl of OXT forms an H-bond with the Asn5 carboxamide side-chain. The lability of the Tyr OH proton of OXT, but not AVP, is in accord with the biological activities of the peptides (OXT 100%, AVP 1%) in the rat uterus assay, suggesting that propylene glycol and DMSO mimic the environment at uterine receptors. 1H-NMR studies in DMSO demonstrate that for AVP there is a perpendicular-plate ring pairing interaction between the Tyr and Phe side-chains in which the hexagonal axis of the Tyr ring interacts with the face of the Phe ring. The present findings are discussed in terms of the proposed "cooperative model" for neurohypophysial hormone action.     

Prolactin promotes oxytocin and vasopressin release by activating neuronal nitric oxide synthase in the supraoptic and paraventricular nuclei

Prolactin (PRL) stimulates the secretion of oxytocin (OXT) and arginine AVP as part of the maternal adaptations facilitating parturition and lactation. Both neurohormones are under the regulation of nitric oxide. Here, we investigate whether the activation of neuronal nitric oxide synthase (nNOS) in the hypothalamo-neurohypophyseal system mediates the effect of PRL on OXT and AVP release and whether these effects operate in males. Plasma levels of OXT and AVP were measured in male rats after the intracerebroventricular injection of PRL or after inducing hyperprolactinemia by placing two anterior pituitary glands under the kidney capsule. NOS activity was evaluated in the paraventricular (PVN) and supraoptic (SON) hypothalamic nuclei by NADPH-diaphorase histochemistry and in hypothalamic extracts by the phosphorylation/inactivation of nNOS at Ser(847). Elevated central and systemic PRL correlated with increased NOS activity in the PVN and SON and with higher OXT and AVP circulating levels. Notably, treatment with 7-nitroindazole, a selective inhibitor of nNOS, prevented PRL-induced stimulation of the release of both neurohormones. Also, phosphorylation of nNOS was reduced in hyperprolactinemic rats, and treatment with bromocriptine, an inhibitor of anterior pituitary PRL secretion, suppressed this effect. These findings suggest that PRL enhances nNOS activity in the PVN and SON, thereby contributing to the regulation of OXT and AVP release. This mechanism likely contributes to the regulation of processes beyond those of female reproduction.     

CD38 and its role in oxytocin secretion and social behavior

Here, we review the functional roles of cyclic ADP-ribose and CD38, a transmembrane protein with ADP-ribosyl cyclase activity, in mouse social behavior via the regulation of oxytocin (OXT) release, an essential component of social cognition. Herein we describe data detailing the molecular mechanism of CD38-dependent OXT secretion in CD38 knockout mice. We also review studies that used OXT, OXT receptor (OXTR), or CD38 knockout mice. Additionally, we compare the behavioral impairments that occur in these knockout mice in relation to the OXT system and CD38. This review also examines autism spectrum disorder (ASD), which is characterized by social and communication impairments, in relation to defects in the OXT system. Two single nucleotide polymorphisms (SNPs) in the human CD38 gene are possible risk factors for ASD via inhibition of OXT function. Further analysis of CD38 in relation to the OXT system may provide a better understanding of the neuroendocrinological roles of OXT and CD38 in the hypothalamus and of the pathophysiology of ASD. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.     

Localisation of oxytocin, vasopressin and parts of precursors in the human neonatal adrenal

Being a possible alternative source for the production of vasopressin (AVP) and oxytocin (OXT), a study was undertaken of the fetal adrenal. The concentrations of these peptides within the fetal adrenal turned out to be low, viz., approx. 1 pg/mg in the rat and within the pg/g range in the human. Immunocytochemistry was performed either on conventional autopsy material kept till 12 years in paraffin blocks, or on more recently obtained formalin or glutaraldehyde-paraformaldehyde fixed material. In both types of material staining was good. In order to localize AVP cells, anti-AVP, an antibody against its associated neurophysin (anti-NSN) or an antibody raised against the c-terminal glycopeptide part of the AVP precursor (anti-GP) was used. OXT cells were localized by means of anti-OXT or an auto-antibody of a multiple sclerosis patient (auto-MS) probably recognizing OXT-neurophysin. The antibodies were characterized on human and rat brain material. In the external zone of the definitive cortex, apart from parenchyma cells, anti-AVP, anti-NSN and anti-GP stained fibre-like structures running in the connective tissue septa and around parenchyma cells and the cytoplasma of these cells. Anti-OXT and auto-MS stained droplets in the cytoplasm of the fetal zone cells. Similar distinct staining patterns for AVP and OXT cells were obtained in human anencephalics. These observations show that the peptides are not derived from the fetal brain, but are rather produced in the fetal adrenal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electric footshocks differentially affect plasma and spinal cord vasopressin and oxytocin levels

Rats exposed for three minutes to repeated electric footshocks showed an approximate 10-fold increase of basal plasma vasopressin (AVP) and oxytocin (OXT) levels. In contrast, spinal AVP and OXT contents measured in the same rats remained unchanged when compared to undisturbed controls. This observation suggests that spinal AVP and OXT do not play a major role in the short-term adaptation of the organism to stress.     

Arginine vasopressin induces periaqueductal gray release of enkephalin and endorphin relating to pain modulation in the rat

Previous study has proven that microinjection of arginine vasopressin (AVP) into periaqueductal gray (PAG) raises the pain threshold, in which the antinociceptive effect of AVP can be reversed by PAG pretreatment with V2 rather than V1 or opiate receptor antagonist. The present work investigated the AVP effect on endogenous opiate peptides, oxytocin (OXT) and classical neurotransmitters in the rat PAG. The results showed that AVP elevated the concentrations of leucine-enkephalin (L-Ek), methionine-enkephalin (M-Ek) and beta-endorphin (beta-Ep), but did not change the concentrations of dynorphinA(1-13) (DynA(1-13)), OXT, classical neurotransmitters including achetylcholine (Ach), choline (Ch), serotonin (5-HT), gamma-aminobutyric acid (GABA), glutamate (Glu), dopamine (DA), norepinephrine (NE) and epinephrine (E), and their metabolic products in PAG perfusion liquid. Pain stimulation increased the concentrations of AVP, L-EK, M-Ek, beta-Ep, 5-HT and 5-HIAA (5-HT metabolic product), but did not influence the concentrations of DynA(1-13), OXT, the other classical neurotransmitters and their metabolic products. PAG pretreatment with naloxone - an opiate receptor antagonist completely attenuated the pain threshold increase induced by PAG administration of AVP, but local pretreatment of OXT or classical neurotransmitter receptor antagonist did not influence the pain threshold increase induced by PAG administration of AVP. The data suggested that AVP in PAG could induce the local release of enkephalin and endorphin rather than dynophin, OXT and classical neurotransmitters to participate in pain modulation.     

Oxytocin actions within the supraoptic and paraventricular nuclei: differential effects on peripheral and intranuclear vasopressin release

In response to forced swimming (FS), AVP is released somato-dendritically within the supraoptic nucleus (SON) and paraventricular nucleus (PVN), but not from neurohypophyseal terminals into blood. Together with AVP, oxytocin (OXT) is released within the SON and PVN. Here, we studied the role of intra-SON and intra-PVN OXT in the regulation of local AVP release and into the blood in male rats. Within the SON, bilateral retrodialysis of an OXT receptor antagonist (OXT-A) increased local AVP release in response to FS [60 s, 21 degrees C, vehicle twofold, not significant (ns); OXT-A: 15-fold increase, P < 0.05] without significantly affecting basal AVP release. In addition, local OXT-A elevated plasma AVP secretion under basal conditions (twofold increase, P < 0.05) without further elevation after FS. Within the PVN, exposure to FS elevated local AVP release, reaching significance only in the OXT-A group (vehicle: 1.4-fold, ns; OXT-A: 1.6-fold increase, P = 0.050). Bilateral OXT-A into the PVN did not affect peripheral AVP secretion either under basal or stress conditions. Basal ACTH concentrations tended to be elevated by local OXT-A within the PVN (1.7-fold increase, P = 0.076). In contrast, the swim-induced ACTH secretion was attenuated after retrodialysis of OXT-A within both the SON (at 5 min) and PVN (at 15 min) (P < 0.05 both) compared with vehicle. The results demonstrate a receptor-mediated effect of OXT within the SON and PVN on local and neurohypophyseal AVP release, which depends upon the activity conditions. Further, while exerting an inhibitory effect on hypothalamo-pituitary-adrenal axis activity under basal conditions, hypothalamic OXT is essential for an adequate acute ACTH response.     

Effects of prostaglandin E2 and D2 on the release of vasopressin and oxytocin

The effects of prostaglandin (PG) E2 and D2 on the plasma levels of arginine-vasopressin (AVP) and oxytocin (OXT) in rabbits, and on the release of the both hormones from the isolated posterior pituitary of rats were examined. An intraventricular administration of PGE2 to a rabbit raised the plasma levels of the both hormones. An intraventricular injection of PGD2 also increased the plasma level of OXT but not that of AVP. The release of AVP and OXT from fragments of the posterior pituitary of a rat was not influenced by perfusion with Eagle MEM medium containing 10(-6) or 10(-5) M PGE2 and D2.     

Localisation of oxytocin,vasopressin and parts of precursors in the human neonatal adrenal

Summary Being a possible alternative source for the production of vasopressin (AVP) and oxytocin (OXT), a study was undertaken of the fetal adrenal. The concentrations of these peptides within the fetal adrenal turned out to be low, viz., approx. 1 pg/mg in the rat and within the pg/g range in the human. Immunocytochemistry was performed either on conventional autopsy material kept till 12 years in paraffin blocks, or on more recently obtained formalin or glutaraldehyde-paraformaldehyde fixed material. In both types of material staining was good. In order to localize AVP cells, anti-AVP, an antibody against its associated neurophysin (anti-NSN) or an antibody raised against the c-terminal glycopeptide part of the AVP precursor (anti-GP) was used. OXT cells were localized by means of anti-OXT or an auto-antibody of a multiple sclerosis patient (auto-MS) probably recognizing OXT-neurophysin. The antibodies were characterized on human and rat brain material. In the external zone of the definitive cortex, apart from parenchyma cells, anti-AVP, anti-NSN and anti-GP stained fibre-like structures running in the connective tissue septa and around parenchyma cells and the cytoplasma of these cells. Anti-OXT and auto-MS stained droplets in the cytoplasm of the fetal zone cells. Similar distinct staining patterns for AVP and OXT cells were obtained in human anencephalics. These observations show that the peptides are not derived from the fetal brain, but are rather produced in the fetal adrenal cortex. Future research will have to determine the physiological meaning of the presence of these peptides in the fetal adrenal, e.g., in their contribution to amniotic fluid peptides, their possible role in fetal stress, steroidogenesis etc. The presence of an alternative source of these peptides in the fetus makes it necessary, further-more, to reconsider their possible functions in the process of labour.In honour of Prof. P. van Duijn     

Effects of Morris water maze testing on the neuroendocrine stress response and intrahypothalamic release of vasopressin and oxytocin in the rat

Adult male Wistar rats were trained in the Morris water maze (MWM) on 3 consecutive days to find a visible platform. Concomitantly, microdialysis samples from the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei were collected in order to monitor local release of the neuropeptides vasopressin (AVP) and oxytocin (OXT), respectively, during controllable swim stress. Additionally, a separate set of animals was equipped with chronic jugular venous catheters to collect blood samples for analyzing plasma concentrations of corticotropin (ACTH) and corticosterone during training in the MWM. As measured by microdialysis, swimming in the MWM caused a significantly increased release of AVP within the PVN and of OXT within the SON on each of the 3 test sessions. In contrast to OXT in the SON, basal AVP concentrations in the PVN tended to rise from day to day. Plasma ACTH and corticosterone were found to be similarly elevated in response to MWM exposure on each of the test sessions. Taken together, these data demonstrate that testing in the MWM is not only associated with a significant activation of the hypothalamo-pituitary-adrenal axis but also with an intrahypothalamic release of AVP and OXT. If compared with findings using repeated forced swimming as an uncontrollable stressor (Wotjak, C.T., Ganster, J., Kohl, G., Holsboer, F., Landgraf, R., Engelmann, M., 1998. Dissociated central and peripheral release of vasopressin, but not oxytocin, in response to repeated swim stress: new insights into the secretory capacities of peptidergic neurons. Neuroscience 85, 1209-1222), the present results suggest that (1) similarities in the release profiles of AVP in the PVN and plasma hormone levels are fairly independent from the controllability of the stressor and seem, thus, to primarily relate to the physical demands of the task, whereas (2) the different intra-SON OXT release profiles might be linked to the controllability of the stressor.     

Oxytocin promotes functional coupling between paraventricular nucleus and both sympathetic and parasympathetic cardioregulatory nuclei

The neuropeptide oxytocin (OXT) facilitates prosocial behavior and selective sociality. In the context of stress, OXT also can down-regulate hypothalamic–pituitary–adrenal (HPA) axis activity, leading to consideration of OXT as a potential treatment for many socioaffective disorders. However, the mechanisms through which administration of exogenous OXT modulates social behavior in stressful environmental contexts are not fully understood. Here, we investigate the hypothesis that autonomic pathways are components of the mechanisms through which OXT aids the recruitment of social resources in stressful contexts that may elicit mobilized behavioral responses. Female prairie voles (Microtus ochrogaster) underwent a stressor (walking in shallow water) following pretreatment with intraperitoneal OXT (0.25 mg/kg) or OXT antagonist (OXT-A, 20 mg/kg), and were allowed to recover with or without their sibling cagemate. Administration of OXT resulted in elevated OXT concentrations in plasma, but did not dampen the HPA axis response to a stressor. However, OXT, but not OXT-A, pretreatment prevented the functional coupling, usually seen in the absence of OXT, between paraventricular nucleus (PVN) activity as measured by c-Fos immunoreactivity and HPA output (i.e. corticosterone release). Furthermore, OXT pretreatment resulted in functional coupling between PVN activity and brain regions regulating both sympathetic (i.e. rostral ventrolateral medulla) and parasympathetic (i.e. dorsal vagal complex and nucleus ambiguous) branches of the autonomic nervous system. These findings suggest that OXT increases central neural control of autonomic activity, rather than strictly dampening HPA axis activity, and provides a potential mechanism through which OXT may facilitate adaptive and context-dependent behavioral and physiological responses to stressors.     

Effect of ethanol and acetaldehyde on the release of arginine-vasopressin and oxytocin from the isolated hypothalamo-hypophyseal system of rats

Effects of ethanol and acetaldehyde on the release of arginine-vasopressin (AVP) and oxytocin (OXT) were examined using a superfusion system of the isolated hypothalamo-hypophyseal complex of rats. The release of both hormones was significantly suppressed by exposing the tissue samples to Eagle MEM medium containing 1.75 and 2.5% ethanol (the maximal suppression: AVP, 30% and 70%; OXT, 30% and 70%, respectively). However, perfusion with medium containing 3.75 and 5.0% ethanol enhanced the release of OXT during exposure to ethanol (the maximal increase, 1,000%) and the release of AVP was increased markedly just after exposure to ethanol was stopped (the maximal increase, 800%). Perfusion with medium containing 50, 100 and 250 microM acetaldehyde did not affect the release.     

The contribution of oxytocin and vasopressin to mammalian social behavior: potential role in autism spectrum disorder

Oxytocin (OT) and arginine-vasopressin (AVP) are 2 peptides that are produced in the brain and released via the pituitary gland to the peripheral blood, where they have diverse physiological functions. In the last 2 decades it has become clear that these peptides also play a central role in the modulation of mammalian social behavior by their actions within the brain. Several lines of evidence suggest their involvement in autism spectrum disorder (ASD), which is known to be associated with impaired social cognition and behavior. Recent clinical trials using OT administration to autistic patients have reported promising results. Here, we aim to describe the main data that suggest a connection between these peptides and ASD. Following a short illustration of several major topics in ASD biology we will (a) briefly describe the oxytocinergic and vasopressinergic systems in the brain, (b) discuss a few compelling cases manifesting the involvement of OT and AVP in mammalian social behavior, (c) describe data supporting the role of these peptides in human social cognition and behavior, and (d) discuss the possibility of the involvement of OT and AVP in ASD etiology, as well as the prospect of using these peptides as a treatment for ASD patients.     

Effects of early life social stress on endocrinology,maternal behavior,and lactation in rats

Exposure to early life stress is a predictor of mental health disorders, and two common forms of early life stress are social conflict and impaired maternal care, which are predominant features of postpartum mood disorders. Exposure of lactating female rats to a novel male intruder involves robust social conflict and induces deficits in maternal care towards the F1 offspring. This exposure is an early life social stressor for female F1 pups that induces inefficient lactation associated with central changes in oxytocin (OXT), prolactin (PRL), and arginine vasopressin (AVP) gene expression in adult F1 females.