Michael Lukas

Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice.

The possibility to improve socio-emotional behaviors in humans by intranasal administration of synthetic oxytocin (OXT) attracts increasing attention, but its uptake into the brain has never been demonstrated so far. Here we used simultaneous microdialysis in both the dorsal hippocampus and amygdala of rats and mice in combination with concomitant blood sampling from the jugular vein to study the dynamics of the neuropeptide in brain extracellular fluid and plasma after its nasal administration. OXT was found to be increased in microdialysates from both the hippocampus and amygdala with peak levels occurring 30-60min after nasal administration. Despite a similar temporal profile of OXT concentrations in plasma, peripheral OXT is unlikely to contribute to dialysate OXT as calculated from in vitro recovery data, indicating a central route of transport. Moreover, intraperitoneal administration of synthetic OXT in identical amounts caused rapid peak levels in brain dialysates and plasma during the first 30min after treatment and a subsequent return toward baseline. While the precise route(s) of central transport remain to be elucidated, our data provide the first evidence that nasally applied OXT indeed reaches behaviorally relevant brain areas, and this uptake is paralleled by changes in plasma OXT.

The Neuropeptide Oxytocin Facilitates Pro-Social Behavior and Prevents Social Avoidance in Rats and Mice

Social avoidance and social phobia are core symptoms of various psychopathologies but their underlying etiology remains poorly understood. Therefore, this study aims to reveal pro-social effects of the neuropeptide oxytocin (OT), under both basal and stress-induced social avoidance conditions in rodents using a social preference paradigm. We initially show that intracerebroventricular (i.c.v.) application of an OT receptor antagonist (OTR-A) in naïve male rats (0.75 μg/5 μl), or mice (20 μg/2 μl), reduced social exploration of a novel con-specific indicative of attenuated social preference. Previous exposure of male rats to a single social defeat resulted in loss of their social preference and social avoidance, which could be restored by i.c.v. infusion of synthetic OT (0.1 μg/5 μl) 20 min before the social preference test. Although the amygdala has been implicated in both social and OT-mediated actions, bilateral OTR-A (0.1 μg/1 μl) or OT (0.01 μg/1 μl) administration into various subnuclei of the amygdala did not affect basal or stress-induced social preference behavior, respectively. Finally, we demonstrate the social specificity of these OT-mediated effects by showing that neither an arginine vasopressin V1a receptor antagonist (0.75 μg/5 μl, i.c.v.) nor the anxiogenic drug pentylenetetrazol (15 mg/kg, i.p.) altered social preference, with OTR-A not affecting non-social anxiety on the elevated plus-maze. Overall, the data indicate that the basal activity of the endogenous brain OT system is sufficient to promote natural occurring social preference in rodents while synthetic OT shows potential to reverse stress-induced social avoidance and might thus be of use for treating social phobia and social dysfunction in humans.

Distinct correlations of vasopressin release within the lateral septum and the bed nucleus of the stria terminalis with the display of intermale aggression

Arginine vasopressin (AVP) has been implicated in a wide variety of social behaviors ranging from affiliation to aggression. However, the precise functional involvement of AVP in intermale aggression is still a matter of debate. In fact, very little is known about AVP release patterns within distinct brain regions during the display of intermale aggression and, in turn, the behavioral consequences of such release. We used intracerebral microdialysis to monitor local AVP release within the lateral septum (LS) and the bed nucleus of the stria terminalis (BST) of adult male Wistar rats during the resident-intruder (RI) test. Resident males were cohabitated with a female prior to the RI test to stimulate intermale aggression toward the intruder male. AVP release within the LS correlated positively with intermale aggression. The specific AVP V1a receptor antagonist d(CH(2))(5)Tyr(Me)AVP (10 microg/ml) administered via retrodialysis (3.3 microl/min, 30 min) into the LS of high-aggressive rats prior to the second RI test, prevented an increase in aggression in the second compared with the first RI test as seen in vehicle-treated high-aggressive rats. In contrast to the LS, AVP release within the BST correlated negatively with intermale aggression. Moreover, retrodialysis of synthetic AVP (1 microg/ml) administered into the BST of high-aggressive rats significantly reduced the display of aggression during the second RI test. These data reveal that AVP can both promote and inhibit intermale aggression, depending upon the brain region in which AVP is released. Although challenging the general view that central AVP release enhances intermale aggression in rodents, our data support a model in which AVP coordinates a range of social behaviors by eliciting region-specific effects.

Maternal separation interferes with developmental changes in brain vasopressin and oxytocin receptor binding in male rats.

Brain vasopressin V(1A) receptors (V(1A)-R) and oxytocin receptors (OT-R) are important modulators of social behaviors. We recently showed that exposure to maternal separation (MS; 3 h daily, postnatal days 1-14) induces changes in social behaviors in juvenile and adult male rats. Here, we hypothesize that MS induces brain region-specific changes in V(1A)-R and OT-R across development, which in turn, may underlie MS-induced changes in social behaviors. We examined the effects of MS on V(1A)-R and OT-R binding in forebrain regions of juvenile (5 weeks), adolescent (8 weeks), and adult (16 weeks) male rats. Robust age-related changes were found for V(1A)-R and OT-R binding in several brain regions. For example, in the lateral septum V(1A)-R binding increased while OT-R binding decreased with age. Most notably, OT-R binding in the caudate putamen showed a 2-fold decrease while OT-R binding in the ventromedial hypothalamus showed a 4-fold increase with age. Importantly, exposure to MS interfered with these developmental changes in several brain regions. Specifically, MS significantly increased V(1A)-R binding in the piriform cortex (at adolescent and adult ages), the lateral septum (at juvenile age), the hypothalamic attack area (at adolescent age), and the dentate gyrus of the hippocampus (at adolescent age), and decreased V(1A)-R binding in the arcuate nucleus (at juvenile age). Moreover, OT-R binding was significantly lower in the agranular cortex (at juvenile and adolescent age), the lateral septum (at adult age) and the caudate putamen (at adult age), but higher in the medial preoptic area (at adolescent age) and ventromedial hypothalamus (at adult age) after exposure to MS. In conclusion, age-dependent changes in V(1A)-R and OT-R binding are likely associated with the maturation of behaviors, such as sexual and aggressive behaviors, while disruption of these changes by MS might contribute to previously observed changes in social behaviors after MS.

Oxytocin mediates rodent social memory within the lateral septum and the medial amygdala depending on the relevance of the social stimulus: Male juvenile versus female adult conspecifics

Brain oxytocin (OXT) plays an important role in short-term social memory in laboratory rodents. Here we monitored local release of OXT and its functional involvement in the maintenance and retrieval of social memory during the social discrimination test. We further assessed, if the local effects of OXT within the medial amygdala (MeA) and lateral septum (LS) on social discrimination abilities were dependent on the biological relevance of the social stimulus, thus comparing male juvenile versus adult female conspecifics. OXT release was increased in the LS of male rats during the retrieval, but not during the acquisition or maintenance, of social memory for male juvenile stimuli. Blockade of OXT activity by intracerebroventricular (ICV) administration of a specific OXT receptor antagonist (OXTR-A, rats: 0.75 μg/5 μl, mice: 2 μg/2 μl) immediately after acquisition of social memory impaired the maintenance of social memory, and consequently discrimination abilities during retrieval of social memory. In contrast, ICV OXTR-A was without effect when administered 20 min prior to retrieval of social memory in both species. Non-social memory measured in the object discrimination test was not affected by ICV OXTR-A in male mice, indicating that brain OXT is mainly required for memory formation in a social context. The biological relevance of the social stimulus seems to importantly determine social memory abilities, as male rats recognized a previously encountered female adult stimulus for at least 2h (versus 60 min for male juveniles), with a region-dependent contribution of endogenous OXT; while bilateral administration of OXTR-A into the MeA (0.1 μg/1 μl) impaired social memory for adult females only, administration of OXTR-A into the LS via retrodialysis (10 μg/ml, 1.0 μl/min) impaired social memory for both male juveniles and female adults. Overall, these results indicate that brain OXT is a critical mediator of social memory in male rodents and that, depending on the biological relevance of the social stimulus, distinct brain regions are recruited to mediate its effects.

Oxytocin and vasopressin in rodent behaviors related to social dysfunctions in autism spectrum disorders.

Autism spectrum disorders (ASD) and social anxiety disorder involve various forms of social deficits like impaired affiliative behavior, social cognition and social approach. Although the neurobiological underpinnings of these disorders are largely unknown, rodent and human studies suggest an involvement of the evolutionary highly conserved oxytocin (OXT) and vasopressin (AVP), as these neuropeptides modulate various aspects of mammalian social behaviors. In this review we summarize the current knowledge regarding the involvement of brain OXT and AVP in rodent social behaviors related to social dysfunctions in ASD. Starting with an introduction into the neurobiology of the central OXT and AVP systems (neuroanatomy, central release, receptor distribution) we describe the distinct roles OXT and AVP play in basic social behaviors in rodents, i.e. affiliative behavior (pair-bonding and maternal behavior), social cognition (social memory), and social approach (social preference or social avoidance). The regulatory capacity of OXT and AVP to modulate social behaviors in various rodent species implies a high translational potential, in particular that dys-regulations in the brain neuropeptide systems may underlie social dysfunctions in ASD. It also suggests that the brain OXT and AVP systems are promising pharmacotherapeutic targets to improve social behaviors and to reverse social deficits.

Early life stress impairs social recognition due to a blunted response of vasopressin release within the septum of adult male rats

Early life stress poses a risk for the development of psychopathologies characterized by disturbed emotional, social, and cognitive performance. We used maternal separation (MS, 3h daily, postnatal days 1-14) to test whether early life stress impairs social recognition performance in juvenile (5-week-old) and adult (16-week-old) male Wistar rats. Social recognition was tested in the social discrimination test and defined by increased investigation by the experimental rat towards a novel rat compared with a previously encountered rat. Juvenile control and MS rats demonstrated successful social recognition at inter-exposure intervals of 30 and 60 min. However, unlike adult control rats, adult MS rats failed to discriminate between a previously encountered and a novel rat after 60 min. The social recognition impairment of adult MS rats was accompanied by a lack of a rise in arginine vasopressin (AVP) release within the lateral septum seen during social memory acquisition in adult control rats. This blunted response of septal AVP release was social stimulus-specific because forced swimming induced a rise in septal AVP release in both control and MS rats. Retrodialysis of AVP (1 μg/ml, 3.3 μl/min, 30 min) into the lateral septum during social memory acquisition restored social recognition in adult MS rats at the 60-min interval. These studies demonstrate that MS impairs social recognition performance in adult rats, which is likely caused by blunted septal AVP activation. Impaired social recognition may be linked to MS-induced changes in other social behaviors like aggression as shown previously.

Chronic Subordinate Colony Housing (CSC) as a Model of Chronic Psychosocial Stress in Male Rats

Chronic subordinate colony housing (CSC) is an adequate and reliable mouse model of chronic psychosocial stress, resulting in reduced body weight gain, reduced thymus and increased adrenal weight, long-lasting anxiety-like behaviour, and spontaneous colitis. Furthermore, CSC mice show increased corticotrophin (ACTH) responsiveness to acute heterotypic stressors, suggesting a general mechanism which allows a chronically-stressed organism to adequately respond to a novel threat. Therefore, the aim of the present study was to extend the CSC model to another rodent species, namely male Wistar rats, and to characterize relevant physiological, immunological, and behavioural consequences; placing particular emphasis on changes in hypothalamo-pituitary-adrenal (HPA) axis responsiveness to an acute heterotypic stressor. In line with previous mouse data, exposure of Wistar rats to 19 days of CSC resulted in a decrease in body weight gain and absolute thymus mass, mild colonic barrier defects and intestinal immune activation. Moreover, no changes in stress-coping behaviour or social preference were seen; again in agreement with the mouse paradigm. Most importantly, CSC rats showed an increased plasma corticosterone response to an acute heterotypic stressor (open arm, 5 min) despite displaying similar basal levels and similar basal and stressor-induced plasma ACTH levels. In contrast to CSC mice, anxiety-related behaviour and absolute, as well as relative adrenal weights remained unchanged in CSC rats. In summary, the CSC paradigm could be established as an adequate model of chronic psychosocial stress in male rats. Our data further support the initial hypothesis that adrenal hyper-responsiveness to ACTH during acute heterotypic stressors represents a general adaptation, which enables a chronically-stressed organism to adequately respond to novel challenges.

Endogenous vasopressin, innate anxiety, and the emission of pro-social 50-kHz ultrasonic vocalizations during social play behavior in juvenile rats

Although the involvement of the neuropeptide arginine vasopressin (AVP) in rodent social interaction is already extensively characterized, little is known about its role in social communication. Rats communicate in the ultrasonic range by means of ultrasonic vocalizations (USV). Depending on developmental stage and affective state, rats emit various distinct types of USV, with appetitive 50-kHz USV being induced by positive social interactions, like juvenile social play, probably serving an affiliative communicative function, namely to (re)establish or induce social proximity. In rats and mice selectively bred for low (LAB) and high (HAB) anxiety-related behavior, the emission of isolation-induced distress USV during maternal deprivation as pups correlates with innate high levels of hypothalamic AVP availability. Moreover, male LAB and HAB rats express deficits in social approach towards conspecifics, together with high and/or abnormal forms of aggression when confronted with harmless opponents, possibly due to a lack of social communication skills. The aim of this study was therefore (1) to investigate and characterize social play behavior and concomitant pro-social 50-kHz USV emission in male and female, juvenile LAB and HAB rats and to compare them to non-selected Wistar (NAB) rats; and (2) to link these findings pharmacologically to the central AVP system via applying an AVP 1a receptor (V1aR) antagonist (0.75 μg; Manning compound) or synthetic AVP (1 ng) into the lateral ventricle of male juvenile NAB rats. Our results show that reduced social play behavior in highly anxious male and female, juvenile HAB rats is accompanied by low amounts of pro-social 50-kHz USV, as compared to respective LAB and NAB rats, possibly reflecting a lack of positive affective states in expectation of or following social interactions in these individuals. Secondly, although synthetic AVP did not alter social play behavior and pro-social 50-kHz USV, we demonstrated for the first time that a blockade of the central AVP system not only reduces juvenile social play behavior, but at the same time pro-social 50-kHz USV emission rates, indicating an involvement of the social neuropeptide in regulating affiliative communication in rodents.

Social preference and maternal defeat-induced social avoidance in virgin female rats: Sex differences in involvement of brain oxytocin and vasopressin

BACKGROUND Research concerning non-reproductive sociability in rodents is mainly restricted to assessing the effects of oxytocin (OXT) and arginine-vasopressin (AVP) in male rats and mice. Comparable studies on natural social preference and social avoidance in females are substantially lacking. NEW METHOD Here, we adapted a behavioral paradigm for monitoring social preference of female rats consisting of two consecutive exposures to either non-social or social stimuli. Further, to induce stimulus-specific social avoidance, female rats were exposed to a single 10-min maternal defeat by a lactating dam. RESULTS Social preference towards same-sex conspecifics in female rats was shown to be independent of the estrous cycle and even more pronounced than in male rats. Intracerebroventricular (icv) application of OXT, AVP, or their selective receptor antagonists or agonists, did not alter naturally-occurring social preference in female rats. Stimulus-specific social avoidance could be induced by prior exposure to a lactating rat: an effect that could not be reversed/overcome by icv OXT. COMPARISON WITH EXISTING METHOD(S) The female social preference paradigm for rats established in this study detected subtle sex differences in social preference behavior of rats. Further, stimulus-specific social deficits could be induced in female rats using an acute exposure to social defeat - as previously observed in male rodents. CONCLUSIONS Female rats show strong social preference behavior, which can be prevented by social defeat, but does not seem to be regulated by the OXT or AVP systems. Accordingly, icv application of synthetic OXT does not reverse maternal defeat-induced social avoidance in female rats.