Sniffing oxytocin: Nose to brain or nose to blood?

Oxytocin (OXT), a hypothalamic neuropeptide, plays a significant modulatory role in social motivation and cognition. Its therapeutic potential has been explored in various clinical trials for conditions such as autism, Prader-Willi syndrome, and schizophrenia, although findings have been inconsistent. A key unresolved question is the mechanism of action—specifically, whether exogenously administered OXT exerts its effects via direct entry into the brain or through peripheral routes. While OXT receptors are widely distributed in the brain, the blood-brain barrier (BBB) is relatively impermeable to peripherally administered OXT. Intranasal administration has been used to bypass the BBB, but the relative contributions of direct brain entry versus peripheral circulation remain unclear. Previous research has shown contradictory results regarding OXT's effects when administered via different routes (intravenous, subcutaneous, intraperitoneal, oral) indicating the complexity of the mechanisms involved and a need to clarify the relative importance of each route. This study aimed to address this by investigating the effects of intranasal OXT administration with and without vasoconstrictor pretreatment to limit peripheral OXT uptake, thereby isolating the neural effects of OXT's direct entry into the brain.

Extensive research has explored the role of oxytocin in social neuroscience and neuropsychopharmacology, highlighting its influence on social motivation and cognition. Clinical trials have explored its therapeutic potential in various psychiatric disorders, with varying results. While the widespread distribution of OXT receptors in the brain is well-established, the relatively low permeability of the BBB to peripherally administered OXT complicates the understanding of its mechanism of action. Intranasal administration has been employed to overcome this limitation, and while the direct entry of OXT into the brain via this route has been confirmed, some studies indicate that peripheral routes could also contribute significantly. Furthermore, previous studies using different administration routes (intravenous, oral, subcutaneous) showed mixed results. Inconsistencies in findings necessitated a rigorous investigation into the specific mechanisms of action, specifically to clarify the relative contributions of direct brain entry versus peripheral circulatory pathways following intranasal administration.

Ninety-six healthy adult males were recruited and randomly assigned to three groups: (1) vasoconstrictor (VC) pretreatment followed by intranasal OXT (VC+OXT); (2) placebo (PLC) pretreatment followed by intranasal OXT (PLC+OXT); and (3) VC pretreatment followed by PLC (VC+PLC). A double-blind, placebo-controlled, between-subject design was used. Blood samples were collected at various time points to measure plasma OXT concentrations. Resting-state EEG (rsEEG) was recorded to assess neural activity, and physiological measures (ECG, electrodermal activity, skin conductance) were also collected. EEG data were preprocessed using EEGLAB, and power spectral analysis was conducted to assess cross-frequency coupling (CFC) patterns. Statistical analyses included repeated-measures ANOVAs and correlation analyses to evaluate the relationship between plasma OXT concentrations and CFC changes. The study used a standardized protocol for intranasal administration and blood sampling, ensuring consistent delivery and measurement.

Intranasal OXT significantly increased plasma OXT concentrations from 15 to 60 minutes post-treatment, but vasoconstrictor pretreatment substantially reduced this increase. Intranasal OXT alone produced widespread increases in delta-beta CFC, mainly observed from 30 minutes post-treatment. Vasoconstrictor pretreatment largely abolished these increases in delta-beta CFC. Importantly, significant positive correlations were found between increases in plasma OXT concentrations and increases in delta-beta CFC following PLC+OXT treatment, but not in the VC+OXT group. These correlations were observed across various time points, further supporting the role of peripheral OXT in influencing CFC. No significant effects were found on other physiological measures such as heart rate variability, skin conductance, or ECG parameters. Analyses at a regional level revealed some remaining effects of OXT on delta-beta CFC even after VC pretreatment, possibly indicating some degree of direct brain entry.

The findings strongly suggest that while intranasal OXT may have some direct effect on the brain, the majority of its influence on delta-beta CFC, a neural marker reflecting interplay between emotional/motivational systems and cognition, is mediated through increased peripheral OXT concentrations. The significant correlations between plasma OXT levels and CFC changes support this conclusion. The vasoconstrictor pretreatment effectively prevented OXT from reaching the peripheral circulation, which in turn minimized the increase in delta-beta CFC. These findings have implications for future research and OXT-based therapeutic interventions. The observed effects on delta-beta CFC are in line with the known role of OXT in modulating social cognition, motivation, and emotion. The minimal effects on other physiological measures suggest a more specific neural mechanism at play.

This study demonstrates that the neural effects of intranasal OXT, as measured by delta-beta CFC, are primarily mediated through increased peripheral OXT concentrations rather than direct brain entry. The use of vasoconstrictor pretreatment provided a novel approach to investigate these distinct pathways. These findings have implications for optimizing OXT administration routes in clinical settings and for minimizing unwanted peripheral side effects. Further research should explore the precise peripheral mechanisms and identify specific brain regions targeted by peripherally-circulating OXT. Investigating individual differences in oxytocinergic responsivity would enhance the understanding of OXT's diverse effects.

The study included only healthy adult males, limiting the generalizability of the findings to other populations (e.g., females, clinical populations). The open-label resting-state measurement might have introduced bias. Furthermore, the study focused on delta-beta CFC and didn't investigate other potential neural or physiological biomarkers. Although the researchers controlled for several potential confounders, other unmeasured factors may have affected the results.