Intranasal Oxytocin Administration Research Articles

Impact of intranasal oxytocin on interoceptive accuracy in alcohol users: an attentional mechanism?

Interoception, i.e. the perception and appraisal of internal bodily signals, is related to the phenomenon of craving, and is reportedly disrupted in alcohol use disorders. The hormone oxytocin influences afferent transmission of bodily signals and, through its potential modulation of craving, is proposed as a possible treatment for alcohol use disorders. However, oxytocin’s impact on interoception in alcohol users remains unknown. Healthy alcohol users (n = 32) attended two laboratory sessions to perform tests of interoceptive ability (heartbeat tracking: attending to internal signals and, heartbeat discrimination: integrating internal and external signals) after intranasal administration of oxytocin or placebo. Effects of interoceptive accuracy, oxytocin administration and alcohol intake, were tested using mixed-effects models. On the tracking task, oxytocin reduced interoceptive accuracy, but did not interact with alcohol consumption. On the discrimination task, we found an interaction between oxytocin administration and alcohol intake: Oxytocin, compared with placebo, increased interoceptive accuracy in heavy drinkers, but not in light social drinkers. Our study does not suggest a pure interoceptive impairment in alcohol users but instead potentially highlights reduced flexibility of internal and external attentional resource allocation. Importantly, this impairment seems to be mitigated by oxytocin. This attentional hypothesis needs to be explicitly tested in future research.

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.

The Effects of Intranasal Administration of Oxytocin on the Behavior of Rats with Different Behavioral Strategies Subjected to Chronic Mild Stress

Two groups of Wistar rats with opposite behavioral strategies – active and passive – were subjected to chronic mild stress. Half of the group of poststress animals received intranasal oxytocin (at a dose of 0.25 IU); their behavior was tested in the Porsolt test and their consumption of a sweet solution was evaluated. Stressed animals with the active behavioral strategy did not respond to oxytocin. Oxytocin partially restored behavior to prestress levels only in animals starting with the passive behavioral strategy.

Oxytocin promotes face-sensitive neural responses to infant and adult faces in mothers

Research utilizing intranasal oxytocin (OT) administration has shown that OT may increase attention and sensitivity to social cues, such as faces. Given the pivotal role of OT in parental behaviors across mammals, the paucity of intranasal OT research investigating responses to social cues in parents and particularly mothers of young children is a critical limitation. In the current study, we recorded cortical event-related potentials (ERPs) to investigate whether intranasal OT affects the early neural responses to emotional faces in mothers of 1-year-old infants. Using a double-blind, within-subjects design, mothers (n = 38) were administered intranasal OT and placebo on separate sessions and presented with happy and sad infant and adult faces while ERP components reflecting face-sensitive brain activation and attention allocation were measured. We hypothesized that ERP responses to faces would be larger in the OT condition and that the effects of OT on ERP responses would be more pronounced for infant faces. The amplitudes of the face-sensitive N170 ERP component were larger in the OT condition to infant and adult faces, but no clear support was found for the hypothesis that the responses to infant faces would be more susceptible to OT effects than the responses to adult faces. The attention-sensitive late positive potential (LPP) component was not modulated by intranasal substance condition. The results are in line with the view that OT acts to enhance the perceptual salience of social and emotional stimuli. Demonstrating such effects in mothers of young children encourages further investigation of the potential of intranasal OT to affect the perception of social cues relevant for parent-child interaction.

Intranasal oxytocin modulates neural functional connectivity during human social interaction.

Oxytocin (OT) modulates social behavior in primates and many other vertebrate species. Studies in non-primate animals have demonstrated that, in addition to influencing activity within individual brain areas, OT influences functional connectivity across networks of areas involved in social behavior. Previously, we used fMRI to image brain function in human subjects during a dyadic social interaction task following administration of either intranasal oxytocin (INOT) or placebo, and analyzed the data with a standard general linear model. Here, we conduct an extensive re-analysis of these data to explore how OT modulates functional connectivity across a neural network that animal studies implicate in social behavior. OT induced widespread increases in functional connectivity in response to positive social interactions among men and widespread decreases in functional connectivity in response to negative social interactions among women. Nucleus basalis of Meynert, an important regulator of selective attention and motivation with a particularly high density of OT receptors, had the largest number of OT-modulated connections. Regions known to receive mesolimbic dopamine projections such as the nucleus accumbens and lateral septum were also hubs for OT effects on functional connectivity. Our results suggest that the neural mechanism by which OT influences primate social cognition may include changes in patterns of activity across neural networks that regulate social behavior in other animals.

Oxytocin enhances observational fear in mice

Empathy is fundamental to human relations, but its neural substrates remain largely unknown. Here we characterize the involvement of oxytocin in the capacity of mice to display emotional state-matching, an empathy-like behavior. When exposed to a familiar conspecific demonstrator in distress, an observer mouse becomes fearful, as indicated by a tendency to freeze and subsequent efforts to escape. Both intranasal oxytocin administration and chemogenetic stimulation of oxytocin neurons render males sensitive to the distress of an unfamiliar mouse. Acute intranasal oxytocin penetrates the brain and enhances cellular activity within the anterior cingulate cortex, whereas chronic administration produces long-term facilitation of observational fear and downregulates oxytocin receptor expression in the amygdala. None of these manipulations affect fear acquired as a result of direct experience with the stressor. Hence, these results implicate oxytocin in observational fear in mice (rather than fear itself) and provide new avenues for examining the neural substrates of empathy.

The effects of adjunctive intranasal oxytocin in patients with schizophrenia

ABSTRACTObjectives: Both human and animal studies have suggested that oxytocin may have therapeutic potential in the treatment of schizophrenia. We evaluated the effects of intranasal oxytocin on cognition and its predictive factors in Japanese patients with schizophrenia.Methods: Subjects were 16 chronic schizophrenia patients who underwent intranasal oxytocin treatment for 3 months and were assessed for changes in severity of clinical symptoms and cognitions. Fifteen of the 16 subjects underwent 3-Tesla magnetic resonance imaging.Results: Oxytocin significantly reduced scores on the positive and negative syndrome scale, especially on the negative symptoms. As for cognition, there was an improvement of the verbal fluency. Furthermore, the change of the negative score in positive and negative syndrome scale showed a negative correlation with the gray matter volumes of the right insula and left cingulate cortex.Conclusions: Our results indicate that daily administration of intranasal oxytocin may be effective for ameliorating clinical symptoms and cognitive functions in chronic schizophrenia patients, and this improvement may be related to the gray matter volume of the right insula and left cingulate cortex.

Effects of Oxytocin on the Levels and Metabolism of Monoamines in the Brain of White Outbred Mice during Long-Term Social Isolation.

The effects of intranasal administration of oxytocin on the levels and metabolism of monoamines in symmetrical structures of the brain of white outbred mice kept under conditions of long-term social isolation were studied by HPLC. Disappearance of initial right-sided asymmetry in the content of dopamine metabolites in the striatum, increased 5-hydroxyacetic acid content in the right striatum, and disappearance of the initial left-sided asymmetry in serotonin level in the cortex were noted; we also found a decrease in norepinephrine content in the left hippocampus with appearance of asymmetry and higher content in the right olfactory tubercle. It can be hypothesized that minor changes in the serotoninergic and dopaminergic systems against the background of high reactivity of noradrenergic system represent specific response of the brain to oxytocin in aggressive animals.

Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism

Recent studies have reported that oxytocin ameliorates behavioral abnormalities in both animal models and individuals with autism spectrum disorders (ASD). However, the mechanisms underlying the ameliorating effects of oxytocin remain unclear. In this study, we examined the effects of intranasal oxytocin on impairments in social interaction and recognition memory in an ASD mouse model in which animals are prenatally exposed to valproic acid (VPA). We found that a single intranasal administration of oxytocin restored social interaction deficits for up to 2h in mice prenatally exposed to VPA, but there was no effect on recognition memory impairments. Additionally, administration of oxytocin across 2weeks improved prenatal VPA-induced social interaction deficits for at least 24h. In contrast, there were no effects on the time spent sniffing in control mice. Immunohistochemical analysis revealed that intranasal administration of oxytocin increased c-Fos expression in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex, but not the hippocampal CA1 and CA3 regions of VPA-exposed mice, suggesting the former regions may underlie the effects of oxytocin. These findings suggest that oxytocin attenuates social interaction deficits through the activation of higher cortical areas and the PVN in an ASD mouse model.

Intranasal oxytocin decreases cross-frequency coupling of neural oscillations at rest

Recent research has suggested a role for the hormone oxytocin in social cognition and behavior. Administration of intranasal oxytocin modulates multiple brain regions during experimental tasks; however, the neural mechanisms that underscore the changes associated with oxytocin administration are yet to be fully elucidated. In a double-blind placebo controlled design using electroencephalography, the effects of intranasal oxytocin on neural oscillations (delta, theta, alpha, beta) and their coupling during the resting state were examined. Prior work suggested that coupling of slow and fast waves are indicative of the integration of motivational and cognitive processes. While neural oscillations were unaffected by oxytocin relative to placebo administration; oxytocin decreased delta-beta, delta-alpha, theta-alpha, and theta-beta coupling. These findings suggest that one mechanism through which intranasal oxytocin may modulate brain and behavior is through affecting the cross-frequency coupling of neural oscillations, a phenomenon that has been associated with specific cognitive and motivational states.

Re: Men's Sexual Response to Female Partner's Intranasal Oxytocin Administration for Hypoactive Sexual Desire Disorder: An Open Prospective Cohort Study.

Re: Men's Sexual Response to Female Partner's Intranasal Oxytocin Administration for Hypoactive Sexual Desire Disorder: An Open Prospective Cohort Study.

Oxytocin modulates human communication by enhancing cognitive exploration

Oxytocin is a neuropeptide known to influence how humans share material resources. Here we explore whether oxytocin influences how we share knowledge. We focus on two distinguishing features of human communication, namely the ability to select communicative signals that disambiguate the many-to-many mappings that exist between a signal’s form and meaning, and adjustments of those signals to the presumed cognitive characteristics of the addressee (“audience design”). Fifty-five males participated in a randomized, double-blind, placebo controlled experiment involving the intranasal administration of oxytocin. The participants produced novel non-verbal communicative signals towards two different addressees, an adult or a child, in an experimentally-controlled live interactive setting. We found that oxytocin administration drives participants to generate signals of higher referential quality, i.e. signals that disambiguate more communicative problems; and to rapidly adjust those communicative signals to what the addressee understands. The combined effects of oxytocin on referential quality and audience design fit with the notion that oxytocin administration leads participants to explore more pervasively behaviors that can convey their intention, and diverse models of the addressees. These findings suggest that, besides affecting prosocial drive and salience of social cues, oxytocin influences how we share knowledge by promoting cognitive exploration.

Intranasal oxytocin and the neural correlates of infant face processing in non-parent women

Event-related potentials (ERPs) have been widely employed to identify different stages of face processing, with recent research probing the neural dynamics of adult’s processing of infant faces. Infant faces represent a salient category of visual stimuli, especially in parents, likely prioritized for processing through activity of the oxytocinergic system. Here we employed a randomized, double-blind, and within-subject crossover study of 24 non-parent women to examine the impact of intranasal oxytocin administration, relative to placebo, on processing infant and adult faces. Our main finding was that, relative to placebo, the P300 ERP elicited by infant faces was greater than the P300 elicited by adult faces in the oxytocin condition. Therefore, oxytocin administration may enhance the allocation of attention towards infant cues, even in non-parent women.

Oxytocin and social functioning

Social anxiety is a form of anxiety characterized by continuous fear of one or more social or performance situations. Although multiple treatment modalities (cognitive behavioral therapy, selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors, benzodiazepines) exist for social anxiety, they are effective for only 60% to 70% of patients. Thus, researchers have looked for other candidates for social anxiety treatment. Our review focuses on the peptide oxytocin as a potential therapeutic option for individuals with social anxiety. Animal research both in nonprimates and primates supports oxytocin's role in facilitation of prosocial behaviors and its anxiolytic effects. Human studies indicate significant associations between social anxiety and oxytocin receptor gene alleles, as well as social anxiety and oxytocin plasma levels. In addition, intranasal administration of oxytocin in humans has favorable effects on social anxiety symptomology. Other disorders, including autism, schizophrenia, and anorexia, have components of social anxiety in their pathophysiology. The therapeutic role of oxytocin for social dysfunction in these disorders is discussed.

Oxytocin administration suppresses hypothalamic activation in response to visual food cues

The aim of this study was to use functional neuroimaging to investigate whether oxytocin modulates the neural response to visual food cues in brain regions involved in the control of food intake. Twenty-four normal weight volunteers received intranasal oxytocin (24 IU) or placebo in a double-blind, randomized crossover study. Measurements were made forty-five minutes after dosing. On two occasions, functional MRI (fMRI) scans were performed in the fasted state; the blood oxygen level-dependent (BOLD) response to images of high-calorie foods versus low-calorie foods was measured. Given its critical role in eating behaviour, the primary region of interest was the hypothalamus. Secondary analyses examined the parabrachial nuclei and other brain regions involved in food intake and food reward. Intranasal oxytocin administration suppressed hypothalamic activation to images of high-calorie compared to low-calorie food (P = 0.0125). There was also a trend towards suppression of activation in the parabrachial nucleus (P = 0.0683). No effects of intranasal oxytocin were seen in reward circuits or on ad libitum food intake. Further characterization of the effects of oxytocin on neural circuits in the hypothalamus is needed to establish the utility of targeting oxytocin signalling in obesity.

Kinetics and Dose Dependency of Intranasal Oxytocin Effects on Amygdala Reactivity

BackgroundCurrent neuroimaging perspectives on a variety of mental disorders emphasize dysfunction of the amygdala. The neuropeptide oxytocin (OXT), a key mediator in the regulation of social cognition and behavior, accumulates in cerebrospinal fluid after intranasal administration in macaques and humans and modulates amygdala reactivity in both species. However, the translation of neuromodulatory OXT effects to novel treatment approaches is hampered by the absence of studies defining the most effective dose and dose–response latency for targeting the amygdala. MethodsTo address this highly relevant issue, a total of 116 healthy men underwent functional magnetic resonance imaging using a randomized, double-blind, placebo-controlled crossover study design. The experimental rationale was to systematically vary dose–test latencies (15–40, 45–70, and 75–100 minutes) and doses of OXT (12, 24, and 48 international units) in order to identify the most robust effects on amygdala reactivity. During functional magnetic resonance imaging, subjects completed an emotional face recognition task including stimuli with varying intensities ranging from low (highly ambiguous) to high (less ambiguous). ResultsOur results indicate that the OXT-induced inhibition of amygdala responses to fear was most effective in a time window between 45 and 70 minutes after administration of a dose of 24 international units. Furthermore, the observed effect was most evident in subjects scoring high on measures of autistic-like traits. Behavioral response patterns suggest that OXT specifically reduced an emotional bias in the perception of ambiguous faces. ConclusionsThese findings provide initial evidence of the most effective dose and dose–test interval for future experimental or therapeutic regimens aimed at targeting amygdala functioning using intranasal OXT administration.

Oxytocin attenuates social and non-social avoidance: Re-thinking the social specificity of Oxytocin

Re-examining decades of the social construal of Oxytocin, the General Approach-Avoidance Hypothesis of Oxytocin (GAAO) predicts that Oxytocin will modulate responding to emotionally-evocative and personally-relevant social and non-social stimuli due to its action on the neural substrate of approach and avoidance motivation. We report the first critical experimental test of GAAO predictions by means of a double-blind intra-nasal administration of Oxytocin vs. placebo in 90 healthy adults (N=90, 50% women). As predicted, we found that among men and women for whom negative emotion (anxious arousal) is motivationally-relevant, intra-nasal administration of Oxytocin reduced behavioral avoidance of emotionally-evocative negatively-valenced social and non-social stimuli, but not closely matched emotionally-neutral stimuli. Findings cannot be explained by extant social theories of Oxytocin. We discuss the implications of the present findings for basic and translational clinical Oxytocin research.

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.

Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women

Oxytocin may influence various human behaviors and the connectivity across subcortical and cortical networks. Previous oxytocin studies are male biased and often constrained by task-based inferences. Here, we investigate the impact of oxytocin on resting-state connectivity between subcortical and cortical networks in women. We collected resting-state functional magnetic resonance imaging (fMRI) data on 26 typically developing women 40 min following intranasal oxytocin administration using a double-blind placebo-controlled crossover design. Independent components analysis (ICA) was applied to examine connectivity between networks. An independent analysis of oxytocin receptor (OXTR) gene expression in human subcortical and cortical areas was carried out to determine plausibility of direct oxytocin effects on OXTR. In women, OXTR was highly expressed in striatal and other subcortical regions, but showed modest expression in cortical areas. Oxytocin increased connectivity between corticostriatal circuitry typically involved in reward, emotion, social communication, language and pain processing. This effect was 1.39 standard deviations above the null effect of no difference between oxytocin and placebo. This oxytocin-related effect on corticostriatal connectivity covaried with autistic traits, such that oxytocin-related increase in connectivity was stronger in individuals with higher autistic traits. In sum, oxytocin strengthened corticostriatal connectivity in women, particularly with cortical networks that are involved in social-communicative, motivational and affective processes. This effect may be important for future work on neurological and psychiatric conditions (for example, autism), particularly through highlighting how oxytocin may operate differently for subsets of individuals.

Combining oxytocin administration and positive emotion inductions: Examining social perception and analytical performance

Intranasal administration of the hypothalamic neuropeptide oxytocin (OT) has, in some studies, been associated with positive effects on social perception and cognition. Similarly, positive emotion inductions can improve a range of perceptual and performance-based behaviors. In this exploratory study, we examined how OT administration and positive emotion inductions interact in their associations with social and analytical performance. Participants (N=124) were randomly assigned to receive an intranasal spray of OT (40IU) or placebo and then viewed one of three videos designed to engender one of the following emotion states: social warmth, pride, or an affectively neutral state. Following the emotion induction, participants completed social perception and analytical tasks. There were no significant main effects of OT condition on social perception tasks, failing to replicate prior research, or on analytical performance. Further, OT condition and positive emotion inductions did not interact with each other in their associations with social perception performance. However, OT condition and positive emotion manipulations did significantly interact in their associations with analytical performance. Specifically, combining positive emotion inductions with OT administration was associated with worse analytical performance, with the pride induction no longer benefiting performance and the warmth induction resulting in worse performance. In sum, we found little evidence for main or interactive effects of OT on social perception but preliminary evidence that OT administration may impair analytical performance when paired with positive emotion inductions.