Effects Of Intranasal Oxytocin Administration Research Articles

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.

Intranasal oxytocin modulates the salience network in aging

Growing evidence supports a role of the neuropeptide oxytocin in promoting social cognition and prosocial behavior, possibly via modulation of the salience of social information. The effect of intranasal oxytocin administration on the salience network, however, is not well understood, including in the aging brain. To address this research gap, 42 young (22.52 ± 3.02 years; 24 in the oxytocin group) and 43 older (71.12 ± 5.25 years; 21 in the oxytocin group) participants were randomized to either self-administer intranasal oxytocin or placebo prior to resting-state functional imaging. The salience network was identified using independent component analysis (ICA). Independent t-tests showed that individuals in the oxytocin compared to the placebo group had lower within-network resting-state functional connectivity, both for left amygdala (MNI coordinates: x = -18, y = 0, z = -15; corrected p < 0.05) within a more ventral salience network and for right insula (MNI coordinates: x = 39, y = 6, z = -6; corrected p < 0.05) within a more dorsal salience network. Age moderation analysis furthermore demonstrated that the oxytocin-reduced functional connectivity between the ventral salience network and the left amygdala was only present in older participants. These findings suggest a modulatory role of exogenous oxytocin on resting-state functional connectivity within the salience network and support age-differential effects of acute intranasal oxytocin administration on this network.

Effect of intranasal oxytocin administration on self-other distinction: Modulations by psychological distance and gender

Preliminary evidence indicates that intranasal oxytocin (OT) administration modulates one’s ability to distinguish oneself from others (i.e., self-other distinction). However, previous findings on this topic are contradictory. The current study addressed this issue by (i) using a novel perceptual matching task examining self-other distinction compared to both close and distant others, and (ii) tentatively exploring potential modulations by gender. In a double-blind, placebo-controlled, randomized OT administration study, 100 participants (50 males and 50 females) were randomized to receive intranasal spray of 24 IU OT or placebo (PL). Afterwards, participants completed a geometry perceptual matching task in which different shapes were paired to the self, a friend, or a stranger. Participants were then asked to judge whether each pair of shapes and labels was correctly matched. The results revealed that compared to PL administration, OT facilitated distinction between the self and a friend in males but not in females. These findings provide insights for debates on the role of OT in self-other distinction by revealing modulations by psychological distance and gender, which have implications for the potential clinical applications of OT.

Effects of intranasal oxytocin administration on empathy and approach motivation in women with borderline personality disorder: a randomized controlled trial

Borderline personality disorder (BPD) is characterized by severe interpersonal dysfunction with problems in social cognition, empathy and social approach. Although the neuropeptide oxytocin is known to regulate complex social cognition and behavior in healthy individuals and clinical populations, there is still a lack of evidence for a potential beneficial effect of oxytocin administration on social cognition and social approach in BPD. Fifty-one women with BPD and 51 matched healthy controls were randomized to a double-blind, placebo-controlled, between-subject experimental trial. We administered a single dose of 24 IU oxytocin or placebo intranasally prior to a standardized task measuring affective and cognitive empathy and approach motivation. All participants were free of hormonal contraception and tested in the mid-luteal phase of their menstrual cycle. In the placebo condition, patients with BPD showed reduced cognitive and affective empathy, and less approach behavior motivation than healthy controls. Intranasal oxytocin significantly increased affective empathy and approach motivation in both BPD patients and healthy controls compared to placebo. More importantly, oxytocin administration led to similar scores between BPD and healthy controls. These findings provide the first evidence for a beneficial effect of oxytocin on deficits in affective empathy and approach motivation of BPD. Our results indicate a beneficial effect of a single dose of oxytocin on affective empathy and approach motivation in women with BPD adapting their level of social functioning to healthy controls. Future clinical trials will need to investigate the long-term effects and effectiveness of oxytocin as an add-on treatment for social impairments in BPD.

Intranasal Oxytocin Administration Reduces Bystanders’ Acceptance of Online Celebrity Bashing

Online celebrity bashing refers to a specific subform of online aggression in which celebrities are the targets of derogatory messages. Recent research focusing on the underlying explanations of why some bystanders turn into perpetrators of celebrity bashing suggests that human capacity for empathy may regulate the involvement in this practice. Bystanders with higher empathy are thought to show more disapproval towards online celebrity bashing, which makes them less likely to join in this practice. However, little is known about the processes of how empathy steers bystanders’ bashing attitudes and behavior. In this study, we examine whether the oxytocinergic system, which forms the neurophysiological foundation of empathy, influences the bystanders’ acceptance of online celebrity bashing. In a double-blind, placebo-controlled experiment, we tested the effects of intranasal oxytocin administration on acceptance of celebrity bashing in men. Sixty participants rated neutral or derogatory comments presented as “tweets.” Electrodermal activity and electrocardiogram of the participants were recorded to control for the stress levels. The results showed that oxytocin administration reduced the acceptance of celebrity bashing. Celebrity bashing was unrelated to stress levels. In natural circumstances oxytocin levels are dependent on the presence and quality of one’s social relationships. As a result, we discuss the importance of facilitating a network of social support in programs addressing the problem of online aggression.

Effects of intranasal oxytocin on distraction as emotion regulation strategy in patients with post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is characterized by difficulty down-regulating emotional responses towards trauma-reminders. The neuropeptide oxytocin may enhance treatment response in PTSD, by dampening excessive fear and improving fear regulation. However, oxytocin effects on (neural correlates of) cognitive emotion regulation abilities have never been investigated in PTSD patients. Therefore, we investigated behavioral and neural effects of intranasal oxytocin administration (40IU) on distraction as emotion regulation strategy in male and female police officers with and without PTSD (n = 76), using a randomized placebo-controlled cross-over fMRI study. The distraction condition consisted of a working memory task while negative affective pictures were presented. Under placebo, male PTSD patients showed decreased right striatal activity during distraction compared to male trauma-exposed controls, which was unaffected by oxytocin. After oxytocin administration, left thalamus activity during distraction was enhanced in all participants, independent of PTSD status or sex. Although left thalamus activity during distraction did not differ between PTSD patients and controls under placebo, it was negatively correlated with error rates within PTSD patients. Furthermore, oxytocin administration increased functional connectivity between the left thalamus and amygdala in PTSD patients and male trauma-exposed controls. Upregulation of thalamus activity during distraction by oxytocin may enhance cognitive emotion regulation abilities during psychotherapy in PTSD, although this should still be investigated in a clinical setting. Our findings open an important research avenue into oxytocin effects on cognitive emotion regulation in PTSD and other psychiatric disorders characterized by deficient emotion regulation abilities. Registered in the Netherlands Trial Registry, registration number: NTR3516

Effect of Intranasal Oxytocin Administration on Human-Directed Social Behaviors in Shelter and Pet Dogs.

A wide variety of evidence has demonstrated that oxytocin is involved in socio-cognitive skills in domestic dogs (Canis familiaris). The purpose was to evaluate the effect of oxytocin administration on socio-cognitive abilities in two populations of dogs with different levels of daily human contact: shelter and pet dogs. Additionally, the effect of different doses of oxytocin (i.e., 16 and 24 IU) was assessed. To this end, dogs were tested on two tasks: a sociability test to assess their social responses and a communicative task focused on the learning of gazing responses. Results showed that pet dogs performed better than shelter dogs on the sociability and the gazing tests showing the relevance of dogs’ previous experience and learning when interacting with people. The administration of 16 IU as well as 24 IU of oxytocin improved the performance on the communicative learning task, producing an increment in gaze duration during extinction. This difference was observed in both pet and shelter dogs. Therefore, oxytocin seems to participate in the persistence of this communicative response. However, the treatment did not modify the behaviors during the sociability test. Furthermore, oxytocin appears to be beneficial to increase the communicative abilities of shelter dogs.

Hippocampal volume modulates salivary oxytocin level increases after intranasal oxytocin administration

Adverse childhood experiences have been shown to affect sensitivity to intranasal oxytocin administration, but the neural mechanisms underlying this altered sensitivity are unclear. The aim of the current study was to examine whether hippocampal abnormalities underlie the effects of adversity on the response to oxytocin administration. In a sample of healthy women (N = 54, age M = 19.63), we examined 1) the association between hippocampal volume and experiences of emotional maltreatment and 2) whether hippocampal volume reductions influence the effect of intranasal oxytocin administration on salivary oxytocin levels. There was no association between hippocampal volume and experiences of emotional maltreatment in the current study. However, we found that larger hippocampal volume was related to a stronger increase in salivary oxytocin level after intranasal oxytocin administration. The hippocampus may be a neural substrate underlying individual differences in sensitivity to oxytocin administration.

Effects of Intranasal Oxytocin Administration on Sexual Functions in Healthy Women: A Laboratory Paradigm.

The neuropeptide oxytocin (OXT) has a variety of physiological functions in maternal behavior and attachment including sexual behavior. Based on animal research and our previous human studies, we set out to investigate intranasal administration of OXT and hypothesized that OXT should be able to modulate sexual function in women. In a double-blind, placebo-controlled, crossover laboratory setting, the acute effects of intranasal administered OXT (24 international units) on sexual drive, arousal, orgasm, and refractory aspects of sexual behavior were analyzed in 27 healthy females (mean age ± SD, 27.52 ± 8.04) together with physiological parameters using vaginal photoplethysmography. Oxytocin administration showed no effect on subjective sexual parameters (eg, postorgasmic tension; P = 0.051). Physiological parameters (vaginal photoplethysmography amplitude and vaginal blood volume) showed a response pattern towards sexual arousal but were not affected by OXT. Using a well-established laboratory paradigm, we did not find that intranasal OXT influences female sexual parameters. Also, sexual drive and other functions were not affected by OXT. These findings indicate that OXT is not able to significantly increase subjective and objective parameters of sexual function in a setting with high internal validity; however, this might be different in a more naturalistic setting.

The effects of intranasal oxytocin on reward circuitry responses in children with autism spectrum disorder

BackgroundIntranasal oxytocin (OT) has been shown to improve social communication functioning of individuals with autism spectrum disorder (ASD) and, thus, has received considerable interest as a potential ASD therapeutic agent. Although preclinical research indicates that OT modulates the functional output of the mesocorticolimbic dopamine system that processes rewards, no clinical brain imaging study to date has examined the effects of OT on this system using a reward processing paradigm. To address this, we used an incentive delay task to examine the effects of a single dose of intranasal OT, versus placebo (PLC), on neural responses to social and nonsocial rewards in children with ASD.MethodsIn this placebo-controlled double-blind study, 28 children and adolescents with ASD (age: M = 13.43 years, SD = 2.36) completed two fMRI scans, one after intranasal OT administration and one after PLC administration. During both scanning sessions, participants completed social and nonsocial incentive delay tasks. Task-based neural activation and connectivity were examined to assess the impact of OT relative to PLC on mesocorticolimbic brain responses to social and nonsocial reward anticipation and outcomes.ResultsCentral analyses compared the OT and PLC conditions. During nonsocial reward anticipation, there was greater activation in the right nucleus accumbens (NAcc), left anterior cingulate cortex (ACC), bilateral orbital frontal cortex (OFC), left superior frontal cortex, and right frontal pole (FP) during the OT condition relative to PLC. Alternatively, during social reward anticipation and outcomes, there were no significant increases in brain activation during the OT condition relative to PLC. A Treatment Group × Reward Condition interaction revealed relatively greater activation in the right NAcc, right caudate nucleus, left ACC, and right OFC during nonsocial relative to social reward anticipation during the OT condition relative to PLC. Additionally, these analyses revealed greater activation during nonsocial reward outcomes during the OT condition relative to PLC in the right OFC and left FP. Finally, functional connectivity analyses generally revealed changes in frontostriatal connections during the OT condition relative to PLC in response to nonsocial, but not social, rewards.ConclusionsThe effects of intranasal OT administration on mesocorticolimbic brain systems that process rewards in ASD were observable primarily during the processing of nonsocial incentive salience stimuli. These findings have implications for understanding the effects of OT on neural systems that process rewards, as well as for experimental trials of novel ASD treatments developed to ameliorate social communication impairments in ASD.

Oxytocin and opioid addiction revisited: old drug, new applications.

This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

Oxytocin and Aggression.

The neuropeptide oxytocin (OT) has a solid reputation as a facilitator of social interactions such as parental and pair bonding, trust, and empathy. The many results supporting a pro-social role of OT have generated the hypothesis that impairments in the endogenous OT system may lead to antisocial behavior, most notably social withdrawal or pathological aggression. If this is indeed the case, administration of exogenous OT could be the "serenic" treatment that psychiatrists have for decades been searching for.In the present review, we list and discuss the evidence for an endogenous "hypo-oxytocinergic state" underlying aggressive and antisocial behavior, derived from both animal and human studies. We furthermore examine the reported effects of synthetic OT administration on aggression in rodents and humans.Although the scientific findings listed in this review support, in broad lines, the link between a down-regulated or impaired OT system activity and increased aggression, the anti-aggressive effects of synthetic OT are less straightforward and require further research. The rather complex picture that emerges adds to the ongoing debate questioning the unidirectional pro-social role of OT, as well as the strength of the effects of intranasal OT administration in humans.

Intranasal Oxytocin to Prevent Posttraumatic Stress Disorder Symptoms: A Randomized Controlled Trial in Emergency Department Patients

BackgroundThere are currently few preventive interventions available for posttraumatic stress disorder (PTSD). Intranasal oxytocin administration early after trauma may prevent PTSD, because oxytocin administration was previously found to beneficially impact PTSD vulnerability factors, including neural fear responsiveness, peripheral stress reactivity, and socioemotional functioning. Therefore, we investigated the effects of intranasal oxytocin administration early after trauma on subsequent clinician-rated PTSD symptoms. We then assessed whether baseline characteristics moderated the intervention’s effects. MethodsWe performed a multicenter, randomized, double-blind, placebo-controlled clinical trial. Adult emergency department patients with moderate to severe acute distress (n = 120; 85% accident victims) were randomized to intranasal oxytocin (8 days/40 IU twice daily) or placebo (8 days/10 puffs twice daily), initiated within 12 days posttrauma. The Clinician-Administered PTSD Scale (CAPS) was administered at baseline (within 10 days posttrauma) and at 1.5, 3, and 6 months posttrauma. The intention-to-treat sample included 107 participants (oxytocin: n = 53; placebo: n = 54). ResultsWe did not observe a significant group difference in CAPS total score at 1.5 months posttrauma (primary outcome) or across follow-up (secondary outcome). Secondary analyses showed that participants with high baseline CAPS scores receiving oxytocin had significantly lower CAPS scores across follow-up than participants with high baseline CAPS scores receiving placebo. ConclusionsOxytocin administration early after trauma did not attenuate clinician-rated PTSD symptoms in all trauma-exposed participants with acute distress. However, participants with high acute clinician-rated PTSD symptom severity did show beneficial effects of oxytocin. Although replication is warranted, these findings suggest that oxytocin administration is a promising preventive intervention for PTSD for individuals with high acute PTSD symptoms.

Notice of Retraction and Replacement: Hofmann et al. Effect of intranasal oxytocin administration on psychiatric symptoms: A meta-analysis of placebo-controlled studies. Psychiatry Research. 2015;228:708-714

Notice of Retraction and Replacement: Hofmann et al. Effect of intranasal oxytocin administration on psychiatric symptoms: A meta-analysis of placebo-controlled studies. Psychiatry Research. 2015;228:708-714

The Effects of Intranasal Oxytocin Administration on Sensitive Caregiving in Mothers with Postnatal Depression

Postnatal depression (PND) is common and negatively affects the mother–infant relationship; oxytocin (OT) has been found to have positive effects on parenting, although psychiatric disorders may reduce these effects. Thus, we explored the role of OT in mothers diagnosed with PND. A within-subject, randomized controlled double-blind design was used to test the effects of nasal administration of OT or placebo on sensitive caregiving. The outcome measures were perceptual and caregiving responses to prerecorded cry sounds, as well as observed maternal sensitivity. We found that in the OT condition mothers with PND were more likely to rate an infant cry as more urgent and they were more likely to indicate they would chose a harsh caregiving strategy in response. There was no effect of OT on maternal sensitive interaction with their own baby. Further research is required prior to consideration of OT administration in depressed mothers of infants.

Oxytocin’s effect on resting-state functional connectivity varies by age and sex

The neuropeptide oxytocin plays a role in social cognition and affective processing. The neural processes underlying these effects are not well understood. Modulation of connectivity strength between subcortical and cortical regions has been suggested as one possible mechanism. The current study investigated effects of intranasal oxytocin administration on resting-state functional connectivity between amygdala and medial prefrontal cortex (mPFC), as two regions involved in social-cognitive and affective processing. Going beyond previous work that largely examined young male participants, our study comprised young and older men and women to identify age and sex variations in oxytocin’s central processes. This approach was based on known hormonal differences among these groups and emerging evidence of sex differences in oxytocin’s effects on amygdala reactivity and age-by-sex-modulated effects of oxytocin in affective processing. In a double-blind design, 79 participants were randomly assigned to self-administer either intranasal oxytocin or placebo before undergoing resting-state functional magnetic resonance imaging. Using a targeted region-to-region approach, resting-state functional connectivity strength between bilateral amygdala and mPFC was examined. Participants in the oxytocin compared to the placebo group and men compared to women had overall greater amygdala–mPFC connectivity strength at rest. These main effects were qualified by a significant three-way interaction: while oxytocin compared to placebo administration increased resting-state amygdala–mPFC connectivity for young women, oxytocin did not significantly influence connectivity in the other age-by-sex subgroups. This study provides novel evidence of age-by-sex differences in how oxytocin modulates resting-state brain connectivity, furthering our understanding of how oxytocin affects brain networks at rest.

Oxytocin Protects Hippocampal Memory and Plasticity from Uncontrollable Stress

The hippocampus is vulnerable to uncontrollable stress and is enriched with oxytocin receptors, but their interactive influences on hippocampal functioning are unknown. This study aimed to determine the effects of intranasal oxytocin administration on stress-induced alterations in synaptic plasticity and spatial memory in male rats. While vehicle-administered stressed rats showed impairment in long-term potentiation, enhancement in long-term depression, and weakened spatial memory, these changes were not observed in oxytocin-administered stressed rats. To reveal the potential signaling mechanism mediating these effects, levels of phosphorylated extracellular signal-regulated kinases (pERK) in the hippocampus was examined. Western blotting showed that oxytocin treatment blocked stress-induced alterations of pERK. Additionally, the oxytocin receptor antagonist L-368,899 inhibited the oxytocin’s protective effects on hippocampal memory to stress. Thus, intranasal administration of oxytocin reduced stress effects on hippocampal synaptic plasticity and memory in rats via acting on oxytocin receptors and regulating ERK activity. This study suggests that exogenous oxytocin may be a therapeutically effective means to counter the detrimental neurocognitive effects of stress.

Effects of intranasal and peripheral oxytocin or gastrin-releasing peptide administration on social interaction and corticosterone levels in rats

The intranasal route of drug administration has gained increased popularity as it is thought to allow large molecules, such as peptide hormones, more direct access to the brain, while limiting systemic exposure. Several studies have investigated the effects of intranasal oxytocin administration in humans as this peptide is associated with prosocial behavior. There are, however, few preclinical studies investigating the effects of intranasal oxytocin administration in rodents. Oxytocin modulates hypothalamic-pituitary-adrenal (HPA) axis functioning and it has been suggested that oxytocin’s ability to increase sociability may occur through a reduction in stress reactivity. Another peptide that appears to influence both social behavior and HPA axis activity is gastrin-releasing peptide (GRP), but it is not known if these GRP-induced effects are related. With this in mind, in the present study, we assessed the effects of intranasal and intraperitoneal oxytocin and GRP administration on social interaction and release of corticosterone in rats. Intranasal and intraperitoneal administration of 20, but not 5μg, of oxytocin significantly increased social interaction, whereas intranasal and peripheral administration of GRP (20 but not 5μg) significantly decreased levels of social interaction. In addition, while intranasal oxytocin (20μg) had no effect on blood corticosterone levels, a marked increase in blood corticosterone levels was observed following intraperitoneal oxytocin administration. With GRP, intranasal (20μg) but not peripheral administration increased corticosterone levels. These findings provide further evidence that intranasal peptide delivery can induce behavioral alterations in rodents which is consistent with findings from human studies. In addition, the peptide-induced changes in social interaction were not linked to fluctuations in corticosterone levels.

RETRACTED: Effect of intranasal oxytocin administration on psychiatric symptoms: A meta-analysis of placebo-controlled studies

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the authors and Editor-in-Chief of the journal. It was brought to the authors' attention that there were several significant data analytic errors linked to the data entry and the software program that was used in the published meta-analysis comparing the effect of intranasal oxytocin versus placebo administration on psychiatric symptoms. Correcting these errors changed the main result of this study. The authors greatly apologize to the journal, the reviewers, and readers for the errors in the original article, and would like to thank the readers who brought the errors to their attention.

Differential Effects of Intranasal Oxytocin Administration On Sexual Functions in Healthy Females: a Laboratory Setting

The neuropeptide oxytocin (OXT) has an impressive variety of physiological functions in maternal and paternal behavior as well as in human sexual behaviors. Based on our previous studies, we hypothesized that OXT should be able to positively influence parameters of sexual function in females. We employed a double-blind, placebo-controlled, crossover design in a laboratory setting involving 27 healthy females (mean±SD: 27.52 ± 8.04). The acute effects of intranasal administered OXT (24 I.U.) on sexual drive, arousal, orgasm and refractory aspects of sexual behavior were analyzed using a psychometric instrument (Acute Sexual Experiences Scale). Additionally we assessed the physiological parameters (e.g. vaginal pulse amplitude, VPA; vaginal blood volume, VBV) using vaginal photoplethysmograph. A confirmatory data analysis, a particularly suitable approach for crossover-design data was chosen for the psychometric parameters. Confirmatory analysis of treatment differences yielded an effect of oxytocin on the ability of having an orgasm in the laboratory ( p > 0.05) as well as on post orgasm contentment ( p > 0.05). Moreover, data indicated a trend concerning the effect of oxytocin on lubrication ( p = 0.085). The physiological parameters (VPA and VBV) showed moderate psychophysiological activation but were not affected by OXT. Our results indicated that intranasal OXT administration in healthy females significantly increased the ability of having orgasm and contentment after orgasm. Women with OXT administration felt easier to have orgasm and more satisfied after sexual intercourse. These findings warrant further investigations, including subjects with sexual and relationship problems.