Advances in the field of intranasal oxytocin research: lessons learned and future directions for clinical research

Abstract

Reports on the modulatory role of the neuropeptide oxytocin on social cognition and behavior have steadily increased over the last two decades, stimulating considerable interest in its psychiatric application. Basic and clinical research in humans primarily employs intranasal application protocols. This approach assumes that intranasal administration increases oxytocin levels in the central nervous system via a direct nose-to-brain route, which in turn acts upon centrally-located oxytocin receptors to exert its behavioral effects. However, debates have emerged on whether intranasally administered oxytocin enters the brain via the nose-to-brain route and whether this route leads to functionally relevant increases in central oxytocin levels. In this review we outline recent advances from human and animal research that provide converging evidence for functionally relevant effects of the intranasal oxytocin administration route, suggesting that direct nose-to-brain delivery underlies the behavioral effects of oxytocin on social cognition and behavior. Moreover, advances in previously debated methodological issues, such as pre-registration, reproducibility, statistical power, interpretation of non-significant results, dosage, and sex differences are discussed and integrated with suggestions for the next steps in translating intranasal oxytocin into psychiatric applications.

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

“…Nevertheless, the neural and behavioral responses to OT administered by the two different routes were very different. While it is possible that this reflects the fact that OT administered intranasally, unlike orally, may additionally produce effects by penetrating into the brain via the olfactory and trigeminal nerves 6 , 14 , we cannot entirely rule out that there might also have been some differential peripheral blood-borne or autonomic effects produced by the two administration routes. The relative amounts of peptide being absorbed into the blood and gastrointestinal system in the two routes of administration could, for example, have contributed to these differences.…”

“…The majority of studies investigating functional effects of OT in both healthy and clinical populations have administered it intranasally. While there have been concerns about whether OT can enter the brain directly via this route 4 , recent animal model 5 – 10 and some supporting human studies 11 – 13 have produced evidence that it can (see also Quintana et al 14 ), possibly via the olfactory and trigeminal nerves 6 . Since several fMRI studies have compared brain activity changes after both intracerebroventricular and intraperitoneal or intravenous OT administration intranasal OT administration also increases concentrations in peripheral blood, observed functional effects may be contributed to via a peripheral route by the peptide entering the blood and subsequently crossing the blood–brain barrier (BBB) after binding to the immunoglobulin RAGE (receptor for advanced glycation end products) 15 , 16 .…”

The Effects of Intranasal Oxytocin on Neural and Behavioral Responses to Social Touch in the Form of Massage

“…Both of these direct and indirect routes of exogenous OT administration can lead to wide ranging changes in neural activity although there may be some regional and functional differences (Ferris et al, 2015;Quintana et al, 2016;Dumais et al, 2017;Tanaka et al, 2018;Martins et al, 2020). A third potential indirect route is via vagal stimulation following effects on receptors in peripheral organs such as the heart and gastrointestinal system (see Quintana et al, 2020 for recent review). An additional potential variable is whether OT itself is having functional effects on responses to touch or if various fragments of the peptide following degradation or derived from other sources are responsible via actions on receptors other than the OT receptor and which might more readily cross the blood brain barrier (see Uvnäs-Moberg et al, 2019).…”

Intranasal oxytocin administration rescues neonatal thermo-sensory deficit in mouse model of Autism

“…We ask whether pharmacological OT treatment could improve thermosensory call behavior in the Magel2 +/−p during neonatal period (P2). Of the two preferred routes to reach the cerebrospinal fluid, and considering the small size of neonate mice, we found more convenient to administrate OT by intranasal (IN) rather than intravenous route ( 43, 44 ). New cohorts of neonatal mice were tested for cool thermosensory call behavior with a similar procedure except that neonates received the treatment in between ambient and cool exposures.…”