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.

Oxytocin (OT) in the central nervous system (CNS) influences social cognition and behavior, making it a candidate for treating clinical disorders such as schizophrenia and autism. Intranasal administration has been proposed as a possible route of delivery to the CNS for molecules like OT. While intranasal administration of OT influences social cognition and behavior, it is not well established whether this is an effective means for delivering OT to CNS targets. We administered OT or its vehicle (saline) to 15 primates (Macaca mulatta), using either intranasal spray or a nebulizer, and measured OT concentration changes in the cerebral spinal fluid (CSF) and in blood. All subjects received both delivery methods and both drug conditions. Baseline samples of blood and CSF were taken immediately before drug administration. Blood was collected every 10 minutes after administration for 40 minutes and CSF was collected once post-delivery, at the 40 minutes time point. We found that intranasal administration of exogenous OT increased concentrations in both CSF and plasma compared to saline. Both delivery methods resulted in similar elevations of OT concentration in CSF, while the changes in plasma OT concentration were greater after nasal spray compared to nebulizer. In conclusion our study provides evidence that both nebulizer and nasal spray OT administration can elevate CSF OT levels.

High-flow interstitial infusion into the brain, which uses bulk fluid flow to achieve a relatively homogeneous drug distribution in the extracellular space of the brain, has the potential to perfuse large volumes of brain. The authors report reproducible long-term delivery of 111In-diethylenetriamine pentaacetic acid-apotransferrin (111In-DTPA-Tf) (molecular mass 81 kD) to Macaca mulatta brain and monitoring with single-photon emission computerized tomography (SPECT). The 111In-DTPA-Tf was infused at 1.9 microl/minute over 87 hours into the frontal portion of the centrum semiovale using a telemetry-controlled, fully implanted pump. On Days 1, 3, 4, 8, 11, and 15 after beginning the infusion, planar and SPECT scans of 111In-DTPA-Tf were obtained. Spread of protein in the brain ranged from 2 to 3 cm and infusion volumes ranged from 3.9 to 6.7 cm3. Perfusion of over one-third of the white matter of the infused hemisphere was achieved. From brain SPECT images of (99m)Tc-hexamethylpropyleneamine oxime, which was administered intravenously before each 111In scan, the authors also found that blood perfusion in the infused region was reduced by less than 5% relative to corresponding noninfused regions. Histological examination at 30 days revealed only mild gliosis limited to the area immediately surrounding the needle tract. These findings indicate that long-term interstitial brain infusion is effective for the delivery of drugs on a multicentimeter scale in the primate brain. The results also indicate that it should be possible to perfuse targeted regions of the brain for extended intervals to investigate the potential utility of neurotrophic factors, antitumor agents, and other materials for the treatment of central nervous system disorders.