“Less is more”: a dose-response account of intranasal oxytocin pharmacodynamics in the human brain

Intranasal oxytocin is receiving increasing research attention as a potential treatment for several brain disorders due to promising preclinical results. However, translating these findings to humans has been hampered by remaining uncertainties about its pharmacodynamics and the methods used to probe its effects in the human brain. Using a dose-response design (9, 18 and 36 IU) and a novel administration device, we demonstrate that oxytocin-induced physiological changes in the amygdala at rest, a key-hub of the brain oxytocin system, follow a dose-response curve with maximal effects for lower doses. Yet, the effects of oxytocin vary by amygdala subdivision, highlighting the need to qualify dose-response curves within subregion. We further link physiological changes with the density of the oxytocin receptor gene mRNA across brain regions, strengthening our confidence in intranasal oxytocin as a valid approach to engage central targets. Finally, we demonstrate that intranasal oxytocin does not disrupt cerebrovascular reactivity; the absence of major vascular confounds corroborates the validity of haemodynamic neuroimaging to probe the effects of intranasal oxytocin in the human brain.