Intranasal Oxytocin Administration Research Articles

Transport of oxytocin to the brain after peripheral administration by membrane-bound or soluble forms of receptors for advanced glycation end-products.

Oxytocin (OT) is a neuropeptide hormone. Single and repetitive administration of OT increases social interaction and maternal behaviour in humans and mammals. Recently, it was found that the receptor for advanced glycation end-products (RAGE) is an OT-binding protein and plays a critical role in the uptake of OT to the brain after peripheral OT administration. Here, we address some unanswered questions on RAGE-dependent OT transport. First, we found that, after intranasal OT administration, the OT concentration increased in the extracellular space of the medial prefrontal cortex (mPFC) of wild-type male mice, as measured by push-pull microperfusion. No increase of OT in the mPFC was observed in RAGE knockout male mice. Second, in a reconstituted in vitro blood-brain barrier system, inclusion of the soluble form of RAGE (endogenous secretory RAGE [esRAGE]), an alternative splicing variant, in the luminal (blood) side had no effect on the transport of OT to the abluminal (brain) chamber. Third, OT concentrations in the cerebrospinal fluid after i.p. OT injection were slightly higher in male mice overexpressing esRAGE (esRAGE transgenic) compared to those in wild-type male mice, although this did not reach statistical significance. Although more extensive confirmation is necessary because of the small number of experiments in the present study, the reported data support the hypothesis that RAGE may be involved in the transport of OT to the mPFC from the circulation. These results suggest that the soluble form of RAGE in the plasma does not function as a decoy in vitro.

In the nose or on the tongue? Contrasting motivational effects of oral and intranasal oxytocin on arousal and reward during social processing

Intranasal oxytocin exerts wide-ranging effects on socioemotional behavior and is proposed as a potential therapeutic intervention in psychiatric disorders. However, following intranasal administration, oxytocin could penetrate directly into the brain or influence its activity via increased peripheral concentrations crossing the blood–brain barrier or influencing vagal projections. In the current randomized, placebo-controlled, pharmaco-imaging clinical trial we investigated effects of 24IU oral (lingual) oxytocin spray, restricting it to peripherally mediated blood-borne and vagal effects, on responses to face emotions in 80 male subjects and compared them with 138 subjects treated intranasally with 24IU. Oral, but not intranasal oxytocin administration increased both arousal ratings for faces and associated brain reward responses, the latter being partially mediated by blood concentration changes. Furthermore, while oral oxytocin increased amygdala and arousal responses to face emotions, after intranasal administration they were decreased. Thus, oxytocin can produce markedly contrasting motivational effects in relation to socioemotional cues when it influences brain function via different routes. These findings have important implications for future therapeutic use since administering oxytocin orally may be both easier and have potentially stronger beneficial effects by enhancing responses to emotional cues and increasing their associated reward.

Chronic oxytocin administration in older men modulates functional connectivity during animacy perception.

While aging is associated with social-cognitive change and oxytocin plays a crucial role in social cognition, oxytocin's effects on the social brain in older age remain understudied. To date, no study has examined the effects of chronic intranasal oxytocin administration on brain mechanisms underlying animacy perception in older adults. Using a placebo-controlled, randomized, double-blinded design in generally healthy older men (mean age (SD) = 69(6); n = 17 oxytocin; n = 14 placebo), this study determined the effects of a four-week intranasal oxytocin administration (24 international units/twice a day) on functional MRI (fMRI) during the Heider-Simmel task. This passive-viewing animacy perception paradigm contains video-clips of simple shapes suggesting social interactions (SOCIAL condition) or exhibiting random trajectories (RANDOM condition). While there were no oxytocin-specific effects on brain fMRI activation during the SOCIAL compared to the RANDOM condition, pre-to-post intervention change in the SOCIAL-RANDOM difference in functional connectivity (FC) was higher in the oxytocin compared to the placebo group in a network covering occipital, temporal, and parietal areas, and the superior temporal sulcus, a key structure in animacy perception. These findings suggest oxytocin modulation of circuits involved in action observation and social perception. Follow-up analyses on this network's connections suggested a pre-to-post intervention decrease in the SOCIAL-RANDOM difference in FC among the placebo group, possibly reflecting habituation to repeated exposure to social cues. Chronic oxytocin appeared to counter this process by decreasing FC during the RANDOM and increasing it during the SOCIAL condition. This study advances knowledge about oxytocin intervention mechanisms in the social brain of older adults.

Oxytocin Increases Prosocial Behavior in Groups of African Lions

Oxytocin modulates mammalian social behavior; however, behavioral responses to intranasal oxytocin can vary across species and contexts. The complexity of social interactions increases with group dynamics, and the impacts of oxytocin on both within- and between-group contexts are unknown. African lions are highly social, living in large groups and forming lifelong egalitarian bonds with related as well as unrelated individuals, yet they are also highly territorial, making them a good model for behavioral investigation. We tested the effects of intranasal administration of oxytocin on social and non-social behaviors within in-group and out-group contexts in African lions. We hypothesized that, post-intranasal oxytocin administration, lions would show an increase in within-group affiliative behavior and tolerance, whereas the effects on responses to out-group stimuli could either produce a heightened response (as seen in some human studies) or an attenuated response (as seen in introductions of unfamiliar individuals). Compared to control trials, lions displayed a significant increase in affiliative within-group behaviors and decreased vigilance toward out-group intruders post-oxytocin administration. These results not only have important implications for understanding the evolution of social circuitry but may have practical applications for conservation efforts requiring the formation of social bonds between unfamiliar individuals.

Changes in endogenous oxytocin levels after intranasal oxytocin treatment in adult men with autism: An exploratory study with long-term follow-up

Intranasal administration of the neuropeptide oxytocin (OT) is increasingly explored as a potential treatment for targeting the core symptoms of autism spectrum disorder (ASD). Previously, interactions of exogenously administered OT with its endogenous production have been demonstrated following single-dose administrations. However, the impact of repeated, long-term OT use on endogenous salivary OT levels is unknown. In this double-blind, randomized, placebo-controlled study with between-subject design, 34 adult men with ASD were either assigned to a four-week treatment of once-daily intranasal OT administrations (24 IU) or placebo. Salivary OT samples were obtained before and after the treatment period as well as at two follow-up sessions, four weeks and one year after cessation of the treatment. Receiving OT intranasally but not placebo reliably increased endogenous salivary levels of OT immediately post-treatment and at the follow-up session four weeks post treatment, indicating an interaction between exogenously administered OT and its endogenous production. Notably, increases in salivary OT at the four-week follow-up session were most pronounced in individuals with larger behavioral improvements in ASD social symptoms. These results suggest that OT's positive effects on social behaviors may lead to a self-perpetuating elevation of OT levels through a feed-forward triggering of its own release. Together, the current investigation provides initial evidence that repeated intranasal administration of OT can induce long-lasting changes in endogenous salivary OT levels, presumably through a positive spiral of OT release.

Intranasal oxytocin affects the stress response to social isolation in sheep

Oxytocin (OT) is a neuropeptide hormone that modulates several social behaviors and can affect the anxiety and stress response. The aim of this study was to determine if administration of intranasal OT affects the stress response to social isolation in sheep. Twenty adult Merino ewes were assigned to two groups; 1) Control group (CG, n = 10), which received an intranasal administration of isotonic saline and 2) Oxytocin-treated group (OTG, n = 10), which received an intranasal administration of OT (24 IU) 40 min before the animals were placed in the social isolation test. During the social isolation test (10 min), the behavior of the sheep was recorded, and blood samples were obtained before and after the test for the determination of cortisol, glucose and serum proteins, and heart rate and surface temperature were recorded. The OTG ewes had a higher cortisol concentration (P = 0.04) after social isolation, tended to vocalize more (P = 0.06) during isolation, and tended to have lower globulin concentrations (P = 0.10) than the CG ewes. Contrary to what we expected, the administration of intranasal OT increased the stress response to social isolation in ewes, which was evidenced by endocrine (greater increase in cortisol concentration), physiological (a tendency to present lower concentration of globulins in blood) and behavioral (a tendency to vocalize more) indicators. This study suggests that the administration of intranasal OT increased the stress response to isolation possibly by strengthening the social bond among ewes.

Intranasal oxytocin administration facilitates the induction of long-term potentiation and promotes cognitive performance of maternally separated rats

Maternal separation (MS) is known to induce permanent changes in the central nervous system and is associated with increased levels of anxiety and cognitive impairments. The neuropeptide oxytocin (OT) has been implicated in a broad spectrum of social and nonsocial and behaviors. Since it plays a significant role in learning and memory and enhances synaptic plasticity, we hypothesized that OT may affect MS-induced changes in synaptic plasticity and cognitive performance.Rat pups underwent MS protocol for 180 min/day from postnatal day (PND) 1−21. OT was administered intranasally (2 μg/μl, 7 days) to control and MS groups from PND 22−34. Plasma corticosterone (CORT) levels, anxiety-like behavior, sociability, learning and memory were measured in adolescent rats. In addition, extracellular evoked field excitatory postsynaptic potentials (fEPSP) were also recorded from hippocampal slices.MS induced higher plasma CORT levels and impaired social interaction, learning and memory. Moreover, MS reduced locomotor activity and increased anxiety-like behavior. Intranasal OT could overcome MS-induced deficits and promoted sociability, learning and memory of MS rats. OT also enhanced locomotor activity in the open field and decreased anxiety-like behavior. Obtained results showed that long term potentiation (LTP) was not induced in MS animals. However, OT injection overcame the MS-induced impairment in LTP generation in CA1 area of the hippocampus.

Oxytocin treatment attenuates amygdala activity in autism: a treatment-mechanism study with long-term follow-up

Intranasal administration of the neuropeptide oxytocin (IN-OT) is increasingly considered as a potential treatment for targeting the core symptoms of autism spectrum disorder (ASD), but the effects of continual use on neural substrates are fairly unexplored and long-term effects are unknown. In this double-blind, randomized, placebo-controlled study, we investigated the effects of single-dose and multiple-dose IN-OT treatment (4 weeks of daily (24 IU) administrations) on brain activity related to processing emotional states. Thirty-eight adult men with ASD (aged between 18 and 35 years) underwent functional magnetic resonance imaging of the posterior superior temporal gyrus (pSTS) and amygdala regions while processing emotional states from point-light biological motion. In line with prior research, a single dose of IN-OT induced a reliable increase in pSTS brain activity during the processing of point-light biological motion, but no consistent long-term changes in pSTS activity were induced after the multiple-dose treatment. In terms of bilateral amygdala, the multiple-dose treatment induced a consistent attenuation in brain activity, which outlasted the period of actual administrations until four weeks and one year post-treatment. Critically, participants with stronger attenuations in amygdala-activity showed greater behavioral improvements, particularly in terms of self-reported feelings of avoidant attachment and social functioning. Together, these observations provide initial insights into the long-lasting neural consequences of chronic IN-OT use on amygdala functioning and provide first indications that the acute versus chronic effects of IN-OT administration may be qualitatively different. Larger studies are however warranted to further elucidate the long-term impact of IN-OT treatment on human neural substrates and its behavioral consequences.

Oxytocin effects on the cognition of women with postpartum depression: A randomized, placebo-controlled clinical trial

BackgroundOne of the most common mental disorders in the perinatal period is postpartum depression (PPD), which is associated with impaired emotional functioning due to alterations in different cognitive aspects including thought and facial emotion recognition (FER). Emotional impairments may affect the interaction and care offered to infants and their later development and therefore interventions with potential to minimize impairments associated with PPD are opportune. Oxytocin (OXT) was shown to have therapeutic properties associated with the promotion of affiliative and pro-social behaviors in different mental disorders. Few studies have assessed its therapeutic potential in PPD. ObjectivesTo assess the effects of the acute administration of intranasal OXT (24 IU) on FER of baby faces and negative thoughts after delivery in mothers with and without PPD. MethodsWe conducted a randomized double-blind, placebo-controlled trial with a crossover design involving mothers with PPD (N = 20) and without PPD (N = 35) in the puerperium. Participants completed a static task of FER of baby faces and a questionnaire of post-natal negative thoughts. ResultsMothers with PPD had increased scores of negative thoughts about motherhood/infants, but no impairments in FER, when compared to healthy mothers. OXT had no effects on the rates of correct judgments or response times in the FER task, but was associated with response biases to facial happiness and the reduction of negative thoughts in mothers with PPD. Discussion/conclusionOXT may have positive effects on maternal affiliative behavior, maternal care, and mother-infant interactions as suggested by changes found in different cognitive aspects, thus minimizing the deleterious effects of PPD on child development.

Oxytocin enhances the recovery of eye-contact induced autonomic arousal: A treatment mechanism study with placebo-controlled design

The neuropeptide oxytocin (OT) is suggested to exert a pivotal role in a variety of complex human behaviors, including trust, attachment, social perception and fear regulation. Previous studies have demonstrated that intranasal administration of OT reduces subjective and neuroendocrine stress responses and dampens amygdala reactivity. OT has also been proposed to modulate activity of the autonomic nervous system.Here, a randomized double-blind, placebo-controlled study (with parallel design) was conducted with 56 healthy adult men to investigate whether a single-dose of OT (24 IU) modulates sympathetic autonomic arousal upon live dyadic gaze interactions. To do so, electrodermal recordings of skin conductance were performed during the engagement of eye contact with a live model in a two-person social context.In accordance to prior research, direct eye gaze elicited a significant enhancement in skin conductance responses, but OT did not specifically enhance or dampen the overall magnitude (amplitude) of the skin conductance response. Administration of OT did facilitate the recovery of skin conductance responses back to baseline (reduced recovery time), indicating a role of OT in restoring homeostatic balance. Notably, the treatment-effect on autonomic recovery was most prominent in participants with low self-reported social responsiveness, indicating that person-dependent factors play an important role in determining OT treatment-responses. Exploratory, it was shown that OT also significantly reduced self-reported feelings of tension and (at trend-level) worrying about how one presents oneself.Together, these observations add further evidence to a role of OT in modulating activity of the autonomic nervous system, primarily by facilitating a restoration of homeostatic balance after stimulus-induced increases in sympathetically-driven autonomic arousal.

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.

Intranasal oxytocin modulates brain responses to voice-identity recognition in typically developing individuals, but not in ASD

Faces and voices are prominent cues for person-identity recognition. Face recognition behavior and associated brain responses can be enhanced by intranasal administration of oxytocin. It is unknown whether oxytocin can also augment voice-identity recognition mechanisms. To find it out is particularly relevant for individuals who have difficulties recognizing voice identity such as individuals diagnosed with autism spectrum disorder (ASD). We conducted a combined behavioral and functional magnetic resonance imaging (fMRI) study to investigate voice-identity recognition following intranasal administration of oxytocin or placebo in a group of adults diagnosed with ASD (full-scale intelligence quotient > 85) and pairwise-matched typically developing (TD) controls. A single dose of 24 IU oxytocin was administered in a randomized, double-blind, placebo-controlled and cross-over design. In the control group, but not in the ASD group, administration of oxytocin compared to placebo increased responses to recognition of voice identity in contrast to speech in the right posterior superior temporal sulcus/gyrus (pSTS/G) — a region implicated in the perceptual analysis of voice-identity information. In the ASD group, the right pSTS/G responses were positively correlated with voice-identity recognition accuracy in the oxytocin condition, but not in the placebo condition. Oxytocin did not improve voice-identity recognition performance at the group level. The ASD compared to the control group had lower right pSTS/G responses to voice-identity recognition. Since ASD is known to have atypical pSTS/G, the results indicate that the potential of intranasal oxytocin to enhance mechanisms for voice-identity recognition might be variable and dependent on the functional integrity of this brain region.

How Can Intranasal Oxytocin Research Be Trusted? A Systematic Review of the Interactive Effects of Intranasal Oxytocin on Psychosocial Outcomes

Over the past two decades, research about the role of oxytocin (OT) in human behavior has grown exponentially. However, a unified theory of OT effects has yet to be developed. Relatedly, growing concerns about the robustness of conclusions drawn in the field have been raised. The current article contributes to this debate by reporting on and discussing key conclusions from a systematic review of published studies addressing the interactive effects of intranasal OT (IN-OT) administration on psychosocial outcomes in a healthy population. The review indicates that (a) tested interactive IN-OT effects were highly heterogeneous; (b) for most published interactions, no replication was attempted; (c) when attempted, replications were largely unsuccessful; (d) significance was unrelated to sample size; (e) statistical power was critically low and unrelated to the rate of significant results; and (f) research practices were characteristic of an exploratory approach. This concerning state of affairs makes it virtually impossible to tease apart true from false interactive IN-OT effects. We provide constructive directions on the basis of this observation and positive predictive value simulations for future research that should help extract true effects from noise and move the IN-OT field forward.

Oxytocin Differentially Modulates Amygdala Responses during Top-Down and Bottom-Up Aversive Anticipation.

The ability to successfully regulate negative emotions such as fear and anxiety is vital for mental health. Intranasal administration of the neuropeptide oxytocin (OXT) has been shown to reduce amygdala activity but to increase amygdala–prefrontal cortex connectivity during exposure to threatening stimuli suggesting that it may act as an important modulator of emotion regulation. The present randomized, between‐subject, placebo‐controlled pharmacological study combines the intranasal administration of OXT with functional magnetic resonance imaging (fMRI) during an explicit emotion regulation paradigm in 65 healthy male participants to investigate the modulatory effects of OXT on both bottom‐up and top‐down emotion regulation. OXT attenuates the activation in the posterior insular cortex and amygdala during anticipation of top‐down regulation of predictable threat stimuli in participants with high trait anxiety. In contrast, OXT enhances amygdala activity during the bottom‐up anticipation of unpredictable threat stimuli in participants with low trait anxiety. OXT may facilitate top‐down goal‐directed attention by attenuating amygdala activity in high anxiety individuals, while promoting bottom‐up attention/vigilance to unexpected threats by enhancing amygdala activity in low anxiety individuals. OXT may thus have the potential to promote an adaptive balance between bottom‐up and top‐down attention systems depending on an individual's trait anxiety level.

Intranasal oxytocin increases respiratory rate and reduces obstructive event duration and oxygen desaturation in obstructive sleep apnea patients: a randomized double blinded placebo controlled study

BackgroundActivation of the oxytocin network has shown benefits in animal models of Obstructive Sleep Apnea (OSA) as well as other cardiorespiratory diseases. We sought to determine if nocturnal intranasal oxytocin administration could have beneficial effects in reducing the duration and/or frequency of obstructive events in obstructive sleep apnea subjects. MethodsTwo sequential standard “in-lab” polysomnogram (PSG) sleep studies were performed in patients diagnosed with OSA that were randomly assigned to initially receive either placebo or oxytocin (40 i.u.) administered intranasally in this double blinded randomized placebo controlled study. Changes in cardiorespiratory events during sleep, including apnea and hypopnea durations and frequency, risk of event-associated bradycardias, arterial oxygen desaturation and respiratory rate were assessed in 2 h epochs following sleep onset. Oxytocin significantly decreased the duration of obstructive events, as well as the oxygen desaturations and incidence of bradycardia that were associated with these events. Notably, oxytocin increased respiratory rate during non-obstructive periods. There were no significant changes in sleep architecture and no adverse effects were reported. ConclusionsOxytocin administration can benefit OSA subjects by reducing the duration and adverse consequences of obstructive events. Oxytocin could also be beneficial in situations involving respiratory depression as oxytocin increased respiratory rate. Additional studies are needed to further understand the mechanisms by which oxytocin promotes these changes in cardiorespiratory function. The long-term efficacy and optimal dose of intranasal oxytocin treatment should also be determined in OSA subjects.ClinicalTrials.gov NCT03148899.

Oxytocin effects on gazing at the human face in retriever dogs

Oxytocin is a neurohormone involved in domestic dogs’ socio-cognitive abilities which appears to be key in the display of gazing behavior as a communicative signal. However, differential effects of oxytocin have been reported in various tasks according to the dogs’ breed. In the present study, we evaluated the effect of the intranasal administration of oxytocin on gazing towards the human face in Golden and Labrador Retrievers. This was assessed during a learning task in which dogs had to gaze at the human face in order to receive food that was visible but inaccessible. Results indicate that only intact dogs who received oxytocin exhibited an increase in gazing behavior, while no differences were observed for neutered dogs. This effect could be related to an interaction between oxytocin and steroid hormones in intact dogs. These findings highlight the importance of including modulating factors, such as breed and neutered status, when studying the mechanisms of oxytocin.

A registered replication study on oxytocin and trust

In an influential paper, Kosfeld et al. (2005) showed that intranasal administration of oxytocin (OT) increases the transfers made by investors in the trust game-suggesting that OT increases trust in strangers. Subsequent studies investigating the role of OT in the trust game found inconclusive effects on the trusting behaviour of investors but these studies deviated from the Kosfeld et al. study in an important way-they did not implement minimal social contact (MSC) between the investors and the trustees in the trust game. Here, we performed a large double-blind and placebo-controlled replication study of the effects of OT on trusting behaviour that yields a power of more than 95% and implements an MSC condition as well as a no-social-contact (NoC) condition. We find no effect of OT on trusting behaviour in the MSC condition. Exploratory post hoc analyses suggest that OT may increase trust in individuals with a low disposition to trust in the NoC condition, but this finding requires confirmation in future research. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 19 October 2018. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.11980368.

Activation of Oxytocin Neurons Improves Cardiac Function in a Pressure-Overload Model of Heart Failure

This work shows long-term restoration of the hypothalamic oxytocin (OXT) network preserves OXT release, reduces mortality, cardiac inflammation, fibrosis, and improves autonomic tone and cardiac function in a model of heart failure. Intranasal administration of OXT in patients mimics the short-term changes seen in animals by increasing parasympathetic-and decreasing sympathetic-cardiac activity. This work provides the essential translational foundation to determine if approaches that mimic paraventricular nucleus (PVN) OXT neuron activation, such as safe, noninvasive, and well-tolerated intranasal administration of OXT, can be beneficial in patients with heart failure.

Oxytocin induces long-lasting adaptations within amygdala circuitry in autism: a treatment-mechanism study with randomized placebo-controlled design.

Intranasal administration of the neuropeptide oxytocin (IN-OT) is increasingly explored as a potential treatment for targeting the core symptoms of autism spectrum disorder (ASD). To date, however, the impact of multiple-dose IN-OT treatment on human neural circuitry is largely unknown, and also the possibility that long-term IN-OT use may induce long-lasting neural adaptations remains unexplored. Using a double-blind, randomized, placebo-controlled, between-subject design (including 38 adult men with ASD), this treatment-mechanism study showed that 4 weeks of daily oxytocin administration (24 IU/day) significantly altered intrinsic (resting-state fMRI) functional connectivity of the amygdala to core regions of the "social brain" (particularly orbitofrontal cortex and superior temporal sulcus) up to 4 weeks and 1 year post treatment. The neural adaptations in functional coupling of the amygdala to the orbitofrontal cortex were associated with reduced feelings of avoidance toward others and-at the trend level-reduced repetitive behaviors. These observations contribute to a deeper mechanistic understanding of the neural substrates that underlie behavioral effects of multiple-dose IN-OT treatment, and provide initial insights into the long-lasting neural consequences of chronic IN-OT use on amygdala circuitry. Future studies are however warranted to further elucidate the long-term impact of IN-OT treatment on human neural circuitry and its behavioral consequences.

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

Could nose-to-brain pathways mediate the effects of peptides such as oxytocin (OT) on brain physiology when delivered intranasally? We address this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebulizer expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing. We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for the treatment of neuropsychiatric disorders.