Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay

Abstract

Oxytocin (OT) is a potential treatment for multiple neuropsychiatric disorders. Since OT is a peptide, delivery by the intranasal (IN) route is the preferred method in clinical studies. Although studies have shown increased cerebrospinal fluid (CSF) OT levels following IN administration, this does not clearly demonstrate that the peripherally administered OT is entering the CSF. For example, it has been suggested that peripheral delivery of OT could lead to central release of endogenous OT. It is also unknown whether the IN route provides for more efficient entry of the peptide into the CSF compared to the IV route which requires blood brain barrier (BBB) penetration. To address these questions, we developed a sensitive and specific quantitative mass spectrometry assay that distinguishes labelled (d5-deuterated) from endogenous (d0) OT. We administered d5-oxytocin (80 IU) to 6 nonhuman primates via IN and IV routes as well as IN saline as a control condition. We measured plasma and CSF concentrations of administered and endogenous OT before (t=0) and after (t=10, 20, 30, 45, 60 minutes) d5-oxytocin dosing. We demonstrate CSF penetrance of d5, exogenous OT delivered by IN and IV administration. Peripheral administration of d5-OT did not lead to increased d0, endogenous OT in the CSF. This suggests that peripheral administration of OT does not lead to central release of endogenous OT. We also did not find that IN administration offered an advantage compared to IV administration with respect to achieving greater CSF concentrations of OT.

The effects of oxytocin on eating behaviour and metabolism in humans

“…Doses used in these studies are therefore supraphysiologic, even when accounting for differences in routes of administration 48 . Evidence indicates that oxytocin at a supraphysiologic dose (80 IU) delivered either intranasally or intravenously crosses the blood brain barrier 16 and therefore might have direct central effects, in addition to peripheral effects. Some of the effects seen at supraphysiologic doses might be due to oxytocin acting at vasopressin receptors 49 .…”

“…Although endogenous oxytocin does not readily cross the blood–brain barrier, behavioural studies indicate that circulating oxytocin might directly enter the hindbrain or act on the vagus nerve 12-15 , and a study in nonhuman primates indicates that oxytocin at supraphysiologic concentrations administered intravenously or intranasally enters the cerebrospinal fluid (CSF) 16 . Furthermore, exogenous oxytocin administration might promote endogenous oxytocin secretion either directly through PVN oxytocin autoreceptors or indirectly through peripheral oxytocin receptors 17,18 .…”

Oxytocin-enforced norm compliance reduces xenophobic outgroup rejection

“…Only recently has neuroscience begun to dissect the biological components of altruistic cooperation and identified oxytocin (OXT), an evolutionarily conserved peptide signaling pathway originating in the mammalian hypothalamus (9), to be a key modulator (10). These insights could be gained because intranasally administered OXT (OXT IN ) penetrates the brain (11)(12)(13) and alters measures of neural and behavioral response (14). Specifically, OXT IN has been revealed to enhance social cooperation (15), generosity (16), and empathy (17,18); to induce an altruistic response bias away from nonsocial toward social priorities (19); and to reinforce parochial preferences for outgroup hostility and ingroup centricity (20,21).…”

The Anorexigenic Neural Pathways of Oxytocin and Their Clinical Implication

“…These reports indicate that the induction of endogenous oxytocin secretion triggered by exogenous oxytocin administration is the main mechanism for its anti-obesity effect. However, neither intranasal nor intravenous injection of oxytocin led to increased endogenous oxytocin in the CSF of monkeys [134]. Further studies of the anorexigenic effect of oxytocin and exogenous oxytocin-induced endogenous oxytocin are needed in the future.…”

“…Although the pharmacokinetics of peripherally injected oxytocin remains unclear, oxytocin is reported to cross the blood-brain barrier [132] by 0.002% [133]. A recent study using rhesus monkeys also demonstrated that the d5-deuterated oxytocin is delivered into cerebrospinal fluid after intranasal and intravenous injection [134].…”