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

Abstract

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.

Fig. 1. Main effect of oral oxytocin (OT) on putamen responses and the relationship between OT blood level change and brain activity.

A The whole-brain voxel-wise analysis revealed a significant main effect of treatment in the right putamen reflecting that OT increased activation in this region relative to PLC (the cluster is presented in color, displayed at p < 0.05_FWE); the overlaying mask in green represents the right putamen from the Brainnetome Atlas which was subsequently used as atlas-based independent region of interest (ROI) to extract beta-estimates for further analyses. B Group difference of OT concentration change. C Correlation between putamen activation to all faces and percentage concentration change of plasma oxytocin.

Fig. 2. Effects of oral oxytocin (OT) on intensity and arousal ratings for different face emotions.

A OT increased intensity ratings to all face emotions. B OT increased emotional arousal ratings to all face emotions but to angry and happy faces more than others. PLC placebo. *p_FDR < 0.05 (all faces), +p_FDR < 0.05 (for specific emotional faces). Bars indicate 95% confidence intervals and medians.

Fig. 3. Mediation analysis for putamen responses to faces and oxytocin (OT) concentrations and behavior ratings.

A Plasma OT concentration % change partially mediated the oxytocin treatment effect on putamen responses to all face emotions. B Putamen responses partially mediated the OT treatment effect on arousal rating to happy faces. PLC placebo. *p < 0.05, **p < 0.01.

Fig. 4. Region of interest (ROI) analysis comparing effects of oral and intranasal oxytocin (OT) on amygdala and putamen responses.

A right amygdala mask from the Brainnetome Atlas. B Oral OT significantly increased activation of the right amygdala, while intranasal oxytocin decreased it. C Right putamen mask from Brainnetome Atlas D oral oxytocin increased the activation of right putamen to all face emotions but intranasal OT had no effect. PLC placebo. *p_FDR < 0.05, **p_FDR < 0.01.

Fig. 5. Comparisons of arousal ratings for face emotions between oral and intranasal oxytocin (OT) administration.

^#p < 0.1, *p < 0.05, **p < 0.01. Bars indicated 95% confidence intervals and medians.