Abstract
Oxytocin may have promise as a treatment for neuropsychiatric disorders. Its therapeutic effect may depend on its ability to enter the brain and bind to the oxytocin receptor. To date, the brain tissue penetrance of intranasal oxytocin has not been demonstrated. In this nonhuman primate study, we administer deuterated oxytocin intranasally and intravenously to rhesus macaques and measure, with mass spectrometry, concentrations of labeled (exogenously administered) and endogenous oxytocin in 12 brain regions two hours after oxytocin administration. Labeled oxytocin is quantified after intranasal (not intravenous) administration in brain regions (orbitofrontal cortex, striatum, brainstem, and thalamus) that lie in the trajectories of the olfactory and trigeminal nerves. These results suggest that intranasal administration bypasses the blood–brain barrier, delivering oxytocin to specific brain regions, such as the striatum, where oxytocin acts to impact motivated behaviors. Further, high concentrations of endogenous oxytocin are in regions that overlap with projection fields of oxytocinergic neurons.
Highlights
Oxytocin may have promise as a treatment for neuropsychiatric disorders
The nine amino acid peptide oxytocin (OT) may represent a novel treatment for neuropsychiatric disorders such as autism[1], mood disorders[2], and addiction[3,4]; the effect of exogenous OT to modulate symptoms related to these disorders is thought to be centrally mediated, with OT acting at its receptor in the brain[2,5]
The work presented here follows our previous study[6] where: (1) we developed a liquid chromatography-mass spectrometrytandem mass spectrometry (LC–MS/MS) assay that accurately measured endogenous OT (d0OT) and administered OT (d5OT) and (2) we demonstrated that deuterated OT, d5OT, reaches the cerebrospinal fluid (CSF) in monkeys when administered by IN and IV routes
Summary
Oxytocin may have promise as a treatment for neuropsychiatric disorders. Its therapeutic effect may depend on its ability to enter the brain and bind to the oxytocin receptor. The nine amino acid peptide oxytocin (OT) may represent a novel treatment for neuropsychiatric disorders such as autism[1], mood disorders[2], and addiction[3,4]; the effect of exogenous OT to modulate symptoms related to these disorders is thought to be centrally mediated, with OT acting at its receptor in the brain[2,5] Given this proposed central effect, evidence of the location and extent of brain parenchyma penetrance of OT after intranasal (IN) or intravenous (IV) administration is important to establish, in order to interpret results of clinical studies with OT. The brain tissue penetrance of OT when delivered by the clinically relevant IN route has not been demonstrated In this nonhuman primate study, we administered d5OT intranasally to rhesus macaques and measured, with a LC–MS/MS assay, concentrations of labeled, as well as endogenous, OT in 12 brain regions. Measuring d5OT brain concentrations >2 h after administration, when CSF d5OT concentrations had been eliminated, may reveal information on OT receptor location
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