Intranasal Oxytocin Administration Research Articles

Intranasal oxytocin alleviates postsurgical pain and comorbid anxiety in mice: Participation of BK(Ca) channels in the hippocampus

The affective dimension in postsurgical pain is still poorly understood. Since neuropeptide oxytocin (OXT) has been implicated in a broad spectrum of pain and negative emotion, we investigated the potential therapeutic effect of intranasal OXT on postsurgical pain and associated anxiety in a mice model of plantar incision. The role of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels was explored by using behavioral pharmacology experiments. We reported that plantar incision in mice induced anxiety-like behaviors and mechanical pain hypersensitivity, with a concurrent decrease of the oxytocin receptor (OTR) in the hippocampus. The immunofluorescence staining showed that the OTR were enriched in pyramidal neurons in CA3 subregion of hippocampus and which were highly co-expressed with the BK(Ca) channels in CA3 subregion. Intranasal OXT significantly ameliorated this postsurgical pain and associated anxiety in a dose-dependent manner, while Intra-CA3 microinjection of OTR antagonist atosiban or the BK(Ca) channel blocker paxilline reduced the effect of OXT in incisional mice. Moreover, intra-CA3 microinjection of BK(Ca) channel opener NS1619 produced a similar effect on postsurgical pain and associated anxiety-like behaviors as those observed following intranasal OXT administration. Conversely, intra-CA3 microinjection of BK(Ca) channel blocker paxilline in normal mice was sufficient to evoke mechanical pain hypersensitivity. Taken together, our data suggested that intranasal OXT administration exerted analgesic and anxiolytic effects in incisional mice by opening BK(Ca) channels in the CA3 subregion of hippocampus.

Sex differences in response to intranasal oxytocin as an adjunctive therapy for patients with severe mental illness

Studies investigating the potential benefits of intranasal oxytocin (INOT) as an add-on treatment for patients with severe mental illness (SMI) have yielded inconsistent results, potentially due to sex differences in response to INOT. This study explored the differential effects of INOT among male and female patients with SMI. A secondary analysis was conducted on a previously studied group of patients who participated in a double-blind, placebo-controlled trial evaluating the impact of INOT as an add-on treatment for patients with SMI. Patients treated in inpatient settings (N = 87) received twice-daily INOT (32IU) or placebo (PLC) for a period of four weeks. Sex moderated the effect of OT/PLC on the Hamilton Rating Scale for Depression (HRDS) (p < 0.001). A significant effect for sex was found in the Hopkins Symptom Checklist–short form (HSCL-11) (p = 0.04) and HRDS (p < 0.001), with females showing greater reductions in anxiety and depression symptoms and severity. This effect was not found for males. We conclude that the addition of INOT to the treatment of patients with SMI in an inpatient setting was beneficial for female patients, particularly reducing depressive symptoms, but not for male patients. Future studies should aim to identify patients who are more likely to benefit from INOT administration.

Oxytocin modulation of explicit pandemic stigma in men with varying social anxiety levels

ObjectiveStigma can create divisions within societies, hindering social cohesion and cooperation. Notably, it has significant public health implications, especially during infectious disease outbreaks like COVID-19. However, little is known about the neural and molecular basis of disease-related stigma and their association with individual differences. MethodsTo address this gap, we performed a double-blind, placebo-controlled, within-subject design study with 70 males, to investigate the effect of intranasal oxytocin (OT) administration on the explicit and implicit processing of disease-related stigma (i.e., COVID-19 stigma). After self-administrated 24 IU of OT or placebo, participants completed a stigma evaluation task and an Implicit Association Test (IAT) to assess the explicit and implicit processes of stigma evaluation, respectively. ResultsThe results showed that oxytocin amplified the differences between participants with high and low social anxiety in explicit COVID-19 stigma, with a higher inclination to attribute the stigmatized status of the stigmatized targets (i.e., COVID-19 related group) to personal causes in high social anxiety individuals, but reduced blame towards the stigmatized targets in low social anxiety individuals under oxytocin compared to placebo treatment. Furthermore, oxytocin strengthened the connections between responsibility attribution and the other processes (i.e., emotional, approach motivation, social deviance). While no modulation of oxytocin on implicit stigma emerged, oxytocin did modulate the associations between specific dimensions of explicit stigma (i.e., social deviance and approach motivation) and implicit stigma. ConclusionIn conclusion, these findings demonstrated that intranasal oxytocin administration could temporally impact the explicit cognitive judgment in disease-related stigma but not the implicit aspect; furthermore, it modulated in distinct ways in individuals with different levels of social anxiety. These findings highlight the trait-dependent oxytocin modulation on disease-related stigma, implying that oxytocin is partly involved in the endocrine system of disease-related stigma. By unraveling the molecular basis of stigma and its association with individual traits, such as social anxiety, we can tailor interventions to meet specific needs of different individuals in the future.

Effects of four-week intranasal oxytocin administration on large-scale brain networks in older adults

Oxytocin (OT) is a crucial modulator of social cognition and behavior. Previous work primarily examined effects of acute intranasal oxytocin administration (IN-OT) in younger males on isolated brain regions. Not well understood are (i) chronic IN-OT effects, (ii) in older adults, (iii) on large-scale brain networks, representative of OT's wider-ranging brain mechanisms. To address these research gaps, 60 generally healthy older adults (mean age = 70.12 years, range = 55–83) were randomly assigned to self-administer either IN-OT or placebo twice daily via nasal spray over four weeks. Chronic IN-OT reduced resting-state functional connectivity (rs-FC) of both the right insula and the left middle cingulate cortex with the salience network but enhanced rs-FC of the left medial prefrontal cortex with the default mode network as well as the left thalamus with the basal ganglia–thalamus network. No significant chronic IN-OT effects were observed for between-network rs-FC. However, chronic IN-OT increased selective rs-FC of the basal ganglia–thalamus network with the salience network and the default mode network, indicative of more specialized, efficient communication between these networks. Directly comparing chronic vs. acute IN-OT, reduced rs-FC of the right insula with the salience network and between the default mode network and the basal ganglia–thalamus network, and greater selective rs-FC of the salience network with the default mode network and the basal ganglia–thalamus network, were more pronounced after chronic than acute IN-OT. Our results delineate the modulatory role of IN-OT on large-scale brain networks among older adults.

Oxytocin treatment rescues irritability-like behavior in Cc2d1a conditional knockout mice.

Irritability, a state of excessive reactivity to negative emotional stimuli, is common in individuals with autism spectrum disorder (ASD). Although it has a significant negative impact of patients' disease severity and quality of life, the neural mechanisms underlying irritability in ASD remain largely unclear. We have previously demonstrated that male mice lacking the Coiled-coil and C2 domain containing 1a (Cc2d1a) in forebrain excitatory neurons recapitulate numerous ASD-like behavioral phenotypes, including impaired social behaviors and pronounced repetitive behaviors. Here, using the bottle-brush test (BBT) to trigger and evaluate aggressive and defensive responses, we show that Cc2d1a deletion increases irritability-like behavior in male but not female mice, which is correlated with reduced number of oxytocin (OXT)-expressing neurons in the paraventricular nucleus (PVN) of the hypothalamus. Intranasal OXT administration or chemogenetic activation of OXT neurons in the PVN rescues irritability-like behavior in Cc2d1a conditional knockout (cKO) mice. Administration of a selective melanocortin receptor 4 agonist, RO27-3225, which potentiates endogenous OXT release, also alleviates irritability-like behavior in Cc2d1a cKO mice, an effect blocked by a specific OXT receptor antagonist, L-368,899. We additionally identify a projection connecting the posterior ventral segment of the medial amygdala (MeApv) and ventromedial nucleus of the ventromedial hypothalamus (VMHvl) for governing irritability-like behavior during the BBT. Chemogenetic suppression of the MeApv-VMHvl pathway alleviates irritability-like behavior in Cc2d1a cKO mice. Together, our study uncovers dysregulation of OXT system in irritability-like behavior in Cc2d1a cKO mice during the BBT and provide translatable insights into the development of OXT-based therapeutics for clinical interventions.

Intranasal Oxytocin Improves Interoceptive Accuracy and Heartbeat-Evoked Potentials During a Cardiac Interoceptive Task

BackgroundInteroception represents perception of the internal bodily state, which is closely associated with social/emotional processing and physical health in humans. Understanding the mechanism that underlies interoceptive processing, particularly its modulation, is therefore of great importance. Given the overlap between oxytocinergic pathways and interoceptive signaling substrates in both peripheral visceral organs and the brain, intranasal oxytocin administration is a promising approach for modulating interoceptive processing. MethodsUsing a double-blind, placebo-controlled, between-participant design, we recruited 72 healthy male participants who performed a cardiac interoceptive task during electroencephalograph and electrocardiograph recording to examine whether intranasal administration of the neuropeptide oxytocin could modulate interoceptive processing. We also collected data in a resting state to examine whether we could replicate previous findings. ResultsThe results showed that in the interoceptive task, oxytocin increased interoceptive accuracy at the behavioral level, which was paralleled by larger heartbeat-evoked potential amplitudes in frontocentral and central regions on the neural level. However, there were no significant effects of oxytocin on electroencephalograph or electrocardiograph during resting state. ConclusionsThese findings suggest that oxytocin may only have a facilitatory effect on interoceptive processing under task-based conditions. Our findings not only provide new insights into the modulation of interoceptive processing via targeting the oxytocinergic system but also provide proof-of-concept evidence for the therapeutic potential of intranasal oxytocin in mental disorders with dysfunctional interoception.

Oxytocin, but not vasopressin, decreases willingness to harm others by promoting moral emotions of guilt and shame

Prosocial and moral behaviors have overlapping neural systems and can both be affected in a number of psychiatric disorders, although whether they involve similar neurochemical systems is unclear. In the current registered randomized placebo-controlled trial on 180 adult male and female subjects, we investigated the effects of intranasal administration of oxytocin and vasopressin, which play key roles in influencing social behavior, on moral emotion ratings for situations involving harming others and on judgments of moral dilemmas where others are harmed for a greater good. Oxytocin, but not vasopressin, enhanced feelings of guilt and shame for intentional but not accidental harm and reduced endorsement of intentionally harming others to achieve a greater good. Neither peptide influenced arousal ratings for the scenarios. Effects of oxytocin on guilt and shame were strongest in individuals scoring lower on the personal distress subscale of trait empathy. Overall, findings demonstrate for the first time that oxytocin, but not vasopressin, promotes enhanced feelings of guilt and shame and unwillingness to harm others irrespective of the consequences. This may reflect associations between oxytocin and empathy and vasopressin with aggression and suggests that oxytocin may have greater therapeutic potential for disorders with atypical social and moral behavior.

Oxytocin and women's health in midlife.

Menopause marks the cessation of fertility and the transition to post-reproductive years. Nearly 1 million US women experience menopause annually, but despite the significant impact it has on their physical and mental health, menopause has been insufficiently studied. Oxytocin is a neurohormone that regulates emotionality, social behaviors, and fundamental physiological systems. Localization of oxytocin receptors in the brain, reproductive tissues, bone, and heart support their role in mental health and potentially sleep, along with reproductive and cardiovascular functions. While experimental data linking oxytocin to behavior and physiology in animals are largely consistent, human data are correlative and inconclusive. As women transition into menopause, oxytocin levels decrease while their susceptibility to mood disorders, poor sleep, osteoporosis, and cardiovascular diseases increases. These concurrent changes highlight oxytocin as a potential influence on the health and mood of women along their reproductive life span. Here, we summarize experimental rodent and non-human primate studies that link oxytocin to reproductive aging and metabolic health and highlight the inconclusive findings in studies of women. Most human studies relied on a single oxytocin assessment in plasma or on intranasal oxytocin administration. The pulsatile release and short half-life of plasma oxytocin limit the validity of these methods. We discuss the need for oxytocin assessments in stable bio-samples, such as urine, and to use valid assays for assessment of associations between changing oxytocin levels and well-being across the reproductive life span. This work has the potential to guide therapeutic strategies that will one day alleviate adverse health outcomes for many women.

Intranasal oxytocin suppresses seizure-like behaviors in a mouse model of NGLY1 deficiency

NGLY1 deficiency is a genetic disease caused by biallelic mutations of the Ngly1 gene. Although epileptic seizure is one of the most severe symptoms in patients with NGLY1 deficiency, preclinical studies have not been conducted due to the lack of animal models for epileptic seizures in NGLY1 deficiency. Here, we observed the behaviors of male and female Ngly1−/− mice by video monitoring and found that these mice exhibit spontaneous seizure-like behaviors. Gene expression analyses and enzyme immunoassay revealed significant decreases in oxytocin, a well-known neuropeptide, in the hypothalamus of Ngly1−/− mice. Seizure-like behaviors in Ngly1−/− mice were transiently suppressed by a single intranasal administration of oxytocin. These findings suggest the therapeutic potential of oxytocin for epileptic seizure in patients with NGLY1 deficiency and contribute to the clarification of the disease mechanism.

Boosting decision-making in rat models of early-life adversity with environmental enrichment and intranasal oxytocin

Impaired decision-making constitutes a fundamental issue in numerous psychiatric disorders. Extensive research has established that early life adversity (ELA) increases vulnerability to psychiatric disorders later in life. ELA in human neonates is associated with changes in cognitive, emotional, as well as reward-related processing. Maternal separation (MS) is an established animal model of ELA and has been shown to be associated with decision-making deficits. On the other hand, enriched environment (EE) and intranasal oxytocin (OT) administration have been demonstrated to have beneficial effects on decision-making in humans or animals. Given these considerations, our investigation sought to explore the impact of brief exposure to EE and intranasal OT administration on the decision-making abilities of adolescent rats that had experienced MS during infancy.The experimental protocol involved subjecting rat pups to the MS regimen for 180 min per day from postnatal day (PND) 1 to PND 21. Then, from PND 22 to PND 34, the rats were exposed to EE and/or received intranasal OT (2 μg/μl) for seven days. The assessment of decision-making abilities, using a rat gambling task (RGT), commenced during adolescence. Our findings revealed that MS led to impaired decision-making and a decreased percentage of advantageous choices. However, exposure to brief EE or intranasal OT administration mitigated the deficits induced by MS and improved the decision-making skills of maternally-separated rats. Furthermore, combination of these treatments did not yield additional benefits. These results suggest that EE and OT may hold promise as therapeutic interventions to enhance certain aspects of cognitive performance.

Social functioning predicts individual changes in EEG microstates following intranasal oxytocin administration: Adouble-blind, cross-over randomized clinical trial.

Oxytocin (OXT) modulates social behaviors. However, the administration of exogenous OXT in humans produces inconsistent behavioral changes, affecting future consideration of OXT as a treatment for autism and other disorders with social symptoms. Inter-individual variability in social functioning traits might play a key role in how OXT changes brain activity and, therefore, behavior. Here, we investigated if inter-individual variability might dictate how single-dose intranasal OXT administration (IN-OXT) changes spontaneous neural activity during the eyes-open resting state. We used a double-blinded, randomized, placebo-controlled, cross-over design on 30 typically developing young adult men to investigate the dynamics of EEG microstates corresponding to activity in defined neural networks. We confirmed previous reports that, at the group level, IN-OXT increases the representation of the attention and salience microstates. Furthermore, we identified a decreased representation of microstates associated with the default mode network. Using multivariate partial least square statistical analysis, we found that social functioning traits associated with IN-OXT-induced changes in microstate dynamics in specific spectral bands. Correlation analysis further revealed that the higher the social functioning, the more IN-OXT increased the appearance of the visual network-associated microstate, and suppressed the appearance of a default mode network-related microstate. The lower the social functioning, the more IN-OXT increases the appearance of the salience microstate. The effects we report on the salience microstate support the hypothesis that OXT regulates behavior by enhancing social salience. Moreover, our findings indicate that social functioning traits modulate responses to IN-OXT and could partially explain the inconsistent reports on IN-OXT effects.

Intranasal oxytocin interacts with testosterone reactivity to modulate parochial altruism

The neuropeptide hormone oxytocin and the steroid hormone testosterone have received attention as modulators of behavior in the context of intergroup conflict. However, to date, their interactive effect has yet to be tested. Here, in a double-blind placebo-control design, 204 participants (102 female participants) self-administrated oxytocin or placebo and completed an experimental economic game modeling intergroup conflict. Salivary testosterone (n = 192) was measured throughout the task to assess endogenous reactivity. As a caveat, even at this sample size, our derived power to detect small effects for 2- and 3-way interactions was relatively low. For male participants, changes in testosterone predicted willingness to sacrifice investments for the betterment of the group. Intranasal administration of oxytocin strongly diminished this effect. In female participants, we found no credible evidence for association between changes in testosterone and investments, rather, oxytocin effects were independent of testosterone. This 3-way interaction was of medium to large effect size (Odds Ratio 5.11). Behavior was also affected by social cues such as signaling of ingroup and outgroup members. Our findings provide insights as to the biological processes underpinning parochial altruism and suggest an additional path for the dual influence of oxytocin and testosterone on human social behavior.

Chronic oxytocin improves neural decoupling at rest in children with autism: an exploratory RCT.

Shifts in peak frequencies of oscillatory neural rhythms are put forward as a principal mechanism by which cross-frequency coupling/decoupling is implemented in the brain. During active neural processing, functional integration is facilitated through transitory formations of "harmonic" cross-frequency couplings, whereas "nonharmonic" decoupling among neural oscillatory rhythms is postulated to characterize the resting, default state of the brain, minimizing the occurrence of spurious, noisy, background couplings. Within this exploratory, randomized, placebo-controlled trial, we assessed whether the transient occurrence of nonharmonic and harmonic relationships between peak-frequencies in the alpha (8-14 Hz) and theta (4-8 Hz) bands is impacted by intranasal administration of oxytocin, a neuromodulator implicated in improving homeostasis and reducing stress/anxiety. To do so, resting-state electroencephalography was acquired before and after 4 weeks of oxytocin administration (12 IU twice-daily) in children with autism spectrum disorder (8-12 years, n = 33 oxytocin; n = 34 placebo). At the baseline, neural assessments of children with autism were compared with those of a matched cohort of children without autism (n = 40). Compared to nonautistic peers, autistic children displayed a lower incidence of nonharmonic alpha-theta cross-frequency decoupling, indicating a higher incidence of spurious "noisy" coupling in their resting brain (p = .001). Dimensionally, increased neural coupling was associated with more social difficulties (p = .002) and lower activity of the parasympathetic "rest & digest" branch of the autonomic nervous system (p = .018), indexed with high-frequency heart-rate-variability. Notably, after oxytocin administration, the transient formation of nonharmonic cross-frequency configurations was increased in the cohort of autistic children (p < .001), indicating a beneficial effect of oxytocin on reducing spurious cross-frequency-interactions. Furthermore, parallel epigenetics changes of the oxytocin receptor gene indicated that the neural effects were likely mediated by changes in endogenous oxytocinergic signaling (p = .006). Chronic oxytocin induced important homeostatic changes in the resting-state intrinsic neural frequency architecture, reflective of reduced noisy oscillatory couplings and improved signal-to-noise properties.

Unlocking potential of oxytocin: improving intracranial lymphatic drainage for Alzheimer's disease treatment.

Background: The impediment to β-amyloid (Aβ) clearance caused by the invalid intracranial lymphatic drainage in Alzheimer's disease is pivotal to its pathogenesis, and finding reliable clinical available solutions to address this challenge remains elusive. Methods: The potential role and underlying mechanisms of intranasal oxytocin administration, an approved clinical intervention, in improving intracranial lymphatic drainage in middle-old-aged APP/PS1 mice were investigated by live mouse imaging, ASL/CEST-MRI scanning, in vivo two-photon imaging, immunofluorescence staining, ELISA, RT-qPCR, Western blotting, RNA-seq analysis, and cognitive behavioral tests. Results: Benefiting from multifaceted modulation of cerebral hemodynamics, aquaporin-4 polarization, meningeal lymphangiogenesis and transcriptional profiles, oxytocin administration normalized the structure and function of both the glymphatic and meningeal lymphatic systems severely impaired in middle-old-aged APP/PS1 mice. Consequently, this intervention facilitated the efficient drainage of Aβ from the brain parenchyma to the cerebrospinal fluid and then to the deep cervical lymph nodes for efficient clearance, as well as improvements in cognitive deficits. Conclusion: This work broadens the underlying neuroprotective mechanisms and clinical applications of oxytocin medication, showcasing its promising therapeutic prospects in central nervous system diseases with intracranial lymphatic dysfunction.

Sexual behaviour of young rams is improved and less stressful after intranasal administration of oxytocin

The aim of this study was to determine if intranasal administration of oxytocin modifies sexual behaviour and the stress response in young rams during sexual tests with ewes in oestrus. Ten rams were used in a cross-over design. At Day 0, the control group (CG, n = 5) received isotonic saline spray intranasally, and the treated group (OTG, n = 5) received oxytocin (24 IU) intranasally, 40 min before the sexual test. At Day 15, the groups were reversed. In each sexual test (20 min) with an oestrous-induced ewe, the sexual behaviour of the young rams was recorded. Serum cortisol concentrations were determined before and after the test. Less flehmen was observed in the OTG, but mounts with ejaculation were increased. The OTG presented lower serum cortisol concentration than the CG. In conclusion, intranasal administration of oxytocin modified the sexual behaviour of rams, evidenced by a decrease in flehmen behaviour and an increase in mounts with ejaculation, making sexual activity more efficacious. In addition, the treatment decreased the stress response of the rams in the sexual tests. Therefore, intranasal administration of oxytocin could be used to increase sexual activity in rams, and with less stress, providing better welfare conditions.

Intranasal oxytocin as an adjunct treatment among patients with severe major depression with and without comorbid borderline personality disorder

IntroductionResults of studies concerning a possible beneficial effect of Intranasal-Oxytocin (IN-OT) as an add-on treatment for patients with major depression (MDD) have been inconsistent. One possible explanation to account for the difference in the effect of IN-OT is comorbid borderline personality disorder (BPD). This randomized controlled study was aimed to explore the differential effect of IN-OT administration among depressive patients with or without comorbid borderline personality disorder. MethodsA secondary analysis was conducted on a specific subset of patients who participated in an RCT evaluating the impact of IN-OT as add-on treatment for patients with severe mental illness. Patients treated in inpatient settings (N = 58) were randomized and double-blindly allocated to receive twice daily IN-OT (32 IU) or placebo for a period of four weeks. The effect of IN-OT on therapy process and outcome was examined among patients with (n = 35) and without (n = 23) comorbid BPD. ResultsAn interaction effect between diagnosis and group was observed on the Outcome Questionnaire-45 (B = 8.93, p = .007). Further analysis revealed that patients without BPD demonstrated significantly greater improvements following OT administration (B = -8.32, p = .001), whereas patients with BPD did not show significant improvement (B = 0.61, p = .76). The interactive pattern was also observed in the Hopkins Symptom Checklist (B = 0.25, p = .02), where patients without BPD demonstrated significantly larger improvements following OT administration (B = -0.29, p = .0009) as compared to placebo, while patients with BPD demonstrated no significant improvement (B = -0.04, p = .55). We did not find a harmful effect of IN-OT administration among patients with MDD and comorbid BPD. ConclusionsPatients with MDD and comorbid BPD benefit less from IN-OT administration as compared to depressed patients without BPD. Future studies should aim to identify patients who are more likely to benefit from IN-OT administration.

Age-dependent effects of oxytocin in brain regions enriched with oxytocin receptors

Although intranasal oxytocin administration to tap into central functions is the most commonly used non-invasive means for exploring oxytocin’s role in human cognition and behavior, the way by which intranasal oxytocin acts on the brain is not yet fully understood. Recent research suggests that brain regions densely populated with oxytocin receptors may play a central role in intranasal oxytocin’s action mechanisms in the brain. In particular, intranasal oxytocin may act directly on (subcortical) regions rich in oxytocin receptors via binding to these receptors while only indirectly affecting other (cortical) regions via their neural connections to oxytocin receptor-enriched regions. Aligned with this notion, the current study adopted a novel approach to test 1) whether the connections between oxytocin receptor-enriched regions (i.e., the thalamus, pallidum, caudate nucleus, putamen, and olfactory bulbs) and other regions in the brain were responsive to intranasal oxytocin administration, and 2) whether oxytocin-induced effects varied as a function of age. Forty-six young (24.96 ± 3.06 years) and 44 older (69.89 ± 2.99 years) participants were randomized, in a double-blind procedure, to self-administer either intranasal oxytocin or placebo before resting-state fMRI. Results supported age-dependency in the effects of intranasal oxytocin administration on connectivity between oxytocin receptor-enriched regions and other regions in the brain. Specifically, compared to placebo, oxytocin decreased both connectivity density and connectivity strength of the thalamus for young participants while it increased connectivity density and connectivity strength of the caudate for older participants. These findings inform the mechanisms underlying the effects of exogenous oxytocin on brain function and highlight the importance of age in these processes.

At the Head and Heart of Oxytocin’s Stress-Regulatory Neural and Cardiac Effects: A Chronic Administration RCT in Children with Autism

Introduction: Intranasal administration of oxytocin presents a promising new approach to reduce disability associated with an autism spectrum disorder diagnosis. Previous investigations have emphasized the amygdala as the neural foundation for oxytocin’s acute effects. However, to fully understand oxytocin’s therapeutic potential, it is crucial to gain insight into the neuroplastic changes in amygdala circuitry induced from chronic oxytocin administrations, particularly in pediatric populations. Objective: We aimed to examine the impact of a 4-week course of intranasal oxytocin on amygdala functional connectivity in children with autism, compared to placebo. Additionally, we investigated whether oxytocin improves cardiac autonomic arousal, as indexed by high-frequency heart rate variability. Methods: Fifty-seven children with autism aged 8–12 years (45 boys, 12 girls) participated in a double-blind, randomized pharmaco-neuroimaging trial involving twice-daily administrations of intranasal oxytocin or placebo. Resting-state fMRI scans and simultaneous, in-scanner heart rate recordings were obtained before, immediately after, and 4 weeks after the nasal spray administration period. Results: Significant reductions in intrinsic amygdala-orbitofrontal connectivity were observed, particularly at the 4-week follow-up session. These reductions were correlated with improved social symptoms and lower cardiac autonomic arousal. Further, oxytocin’s neural and cardiac autonomic effects were modulated by epigenetic modifications of the oxytocin receptor gene. The effects were more pronounced in children with reduced epigenetic methylation, signifying heightened expression of the oxytocin receptor. Conclusion: These findings underscore that a 4-week oxytocin administration course decreases amygdala connectivity and improves cardiac autonomic balance. Epigenetic modulators may explain inter-individual variation in responses to oxytocin.

Four-week intranasal oxytocin administration reduces attachment avoidance in older women

The neuropeptide oxytocin (OT) serves as a critical modulator of social cognition and social behavior. Adult attachment is an affiliative process crucial for social interaction across adulthood. Insecure adult attachment comprises two broad dimensions, attachment anxiety and attachment avoidance. Both these dimensions of attachment are currently understudied regarding OT modulation, and especially in older adults. The present study determined the effects of chronic intranasal OT administration on adult attachment in generally healthy older women and men (aged 55–95 years). Embedded in a larger project, participants were randomly assigned to self-administer 24 international units of either OT or a placebo (P) intranasally twice daily for four weeks. The Experiences in Close Relationships Scale assessed adult attachment (anxiety and avoidance) pre- and post-treatment. There was no significant pre- to post-treatment change in attachment avoidance overall, but the treatment x timepoint x sex interaction was significant, in that women (but not men) in the OT (vs. P) group reported decreased attachment avoidance. No comparable effects were observed for attachment anxiety. Results suggest that older women may benefit from chronic intranasal OT treatment by experiencing less attachment avoidance in their adult relationships.

Effect of intranasal oxytocin on palatable food consumption and c-Fos immunoreactivity in relevant brain areas in rats

Peripheral and central injections of oxytocin (OT) in laboratory animals decrease eating for energy and palatability, but the hypophagic response is dependent on the administration route. Human studies rely on intranasal (IN) administration of the peptide, the route underutilized in OT animal feeding studies thus far. Therefore, we examined the effect of IN OT on various aspects of food consumption in rats: (a) overnight deprivation-induced standard chow intake, (b) episodic (2-h) consumption of calorie-dense and palatable high-fat high-sugar (HFHS) chow, (c) 2-h episodic intake of palatable and calorie-dilute sucrose and Intralipid solutions, and (d) 2-h sucrose solution intake in rats habituated to ingesting this solution daily for several weeks. Finally, we assessed c-Fos changes in response to the acute IN OT administration in rats habituated to daily sugar consumption. We found that IN 20μg OT decreased deprivation-induced intake of standard chow and HFHS chow in nondeprived rats without affecting water consumption. IN OT also reduced 2-hour episodic fluid consumption of sucrose, but not Intralipid. In the habitual sugar consumption paradigm, acute IN OT diminished sucrose solution intake in animals accustomed to the 2-hour/day sucrose meal regimen. In rats habitually consuming sucrose, IN OT altered c-Fos immunoreactivity in brain areas related to energy homeostasis and reward, including the central nucleus of the amygdala, the hypothalamic paraventricular and the arcuate nuclei. We conclude that IN OT is an effective appetite suppressant for carbohydrate/sugar diets in rats and its effects involve feeding-related brain circuits.