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

D A Martins,M Howard,N Mazibuko,D Murphy,S C R Williams,S Maltezos,A Fotopoulou,Y Paloyelis,F Zelaya,U Schuschnig,M Mehta,G Mcalonan,S Vasilakopoulou,J Loveridge,A Oates,S Wastling

doi:10.1038/s41467-020-14845-5

Abstract

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.

Highlights

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 to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing
We have previously demonstrated the sensitivity of arterial spin labelling (ASL) magnetic resonance imaging (MRI) in quantifying changes in brain’s physiology after intranasal OT administration[16], as reflected in changes in regional cerebral blood flow at rest, which provide a quantitative, non-invasive pharmacodynamic marker of the effects of acute doses of psychoactive drugs[27,28], with highspatial resolution and excellent temporal reproducibility[29]
There were no significant main effects of treatment or time-interval, and no significant treatment × time-interval effects on heart rate or on any time domain, frequency domain or nonlinear measures of heart-rate variability (Supplementary Table 5). This is the first in man study to investigate the pharmacodynamics of synthetic oxytocin on resting regional cerebral blood flow (rCBF) over an extended period of time when administered intravenously, with a nebulizer or a standard nasal spray

Summary

Introduction

It is possible that the small amount of synthetic OT that crosses the BBB from systemic circulation[15] may be sufficient to induce functional effects in the brain, either by directly activating receptors in the brain or by stimulating OT autoreceptors on OT-synthesizing hypothalamic neurons to induce the release endogenous OT15. These mechanisms might account for the effects of peripherally administered OT (e.g. intravenous infusion) on behaviour[21,22,23,24]. To achieve significant translational advances, we need to confirm whether nasal pathways can be used to target the central OT system and whether they offer any advantage in relation to alternative methods

Methods

Results

Conclusion