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. As 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 unequivocably 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 intravenous (IV) route, which requires blood-brain barrier penetration. To address these questions, we developed a sensitive and specific quantitative mass spectrometry assay that distinguishes labeled (d5-deuterated) from endogenous (d0) OT. We administered d5 OT (80 IU) to six 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 and 60 min) d5 OT 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.

Conflict of interest statement

Disclosures: The authors have no conflicts to report.

Figures

Figure 1

d5 oxytocin (OT) concentrations: Time course of d5 oxytocin (OT) concentrations in monkey cerebrospinal fluid (CSF, panels A and B) and plasma (panels C and D) after intranasal and intravenous administration of 80 IU d5 OT (N = 6). Dashed line indicates the limit of quantification (10 ng/L). Insets magnify time course at lower concentrations of d5 OT in CSF.

Figure 2

Significant elevations in Log 10 CSF d5 OT concentrations (SEM) at T= 60 minutes after IV (p<0.005) and IN (p=0.030) administration of 80 IU d5 OT.

Figure 3

d0 oxytocin (OT) concentrations: Time course of d0 oxytocin (OT) in monkey cerebrospinal fluid (CSF) at baseline and after A) intranasal d5 OT, B) intravenous d5 OT and C) intranasal saline administration (N = 5–6). Dashed line indicates lowest limit of quantification (10 ng/L).

Figure 4

Correlation of plasma d5 OT levels and CSF d5 OT levels with Spearman’s rho (rs) after a) IN and b) IV d5 OT delivery.

Figure 5

Correlation of plasma d5 OT levels and CSF d0 OT levels with Spearman’s rho (rs) after a) IN and b) IV d5 OT delivery.

Figure 6

Correlation of CSF d5 OT levels and CSF d0 OT levels with Spearman’s rho (rs) after a) IN and b) IV d5 OT delivery.

Figure 7

Pharmacokinetic parameters: Boxplots depicting median and ranges for maximum concentrations (Cmax; panels A and D), times of maximum concentration occurrence (Tmax; panels B and E) and areas under the curve (AUC0 to 60min; panels C and F) of d5 oxytocin (OT) in monkey plasma and cerebrospinal fluid after intravenous and intranasal d5 OT administration (80 IU; N=4–6). P-values for paired t-test administration route comparisons are noted in each panel.