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

Molecular Psychiatry volume 23, pages 115–122 (2018)Cite this article

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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.

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Acknowledgements

We thank Ms Karen Smith, National Institutes of Health Library for bibliographic assistance. The work was supported by a Bench-to-Bedside (B2B) Grant (PI: Lee) funded by the National Institutes of Health (NIH) Office of Behavioral and Social Sciences Research (OBSSR), NIH intramural funding ZIA-AA000218 (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology; PI: Leggio), jointly supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Intramural Research Program (IRP) of the National Institute on Drug Abuse (NIDA) and ZIA MH002928-01 (Unit on Learning and Decision Making; PI: Averbeck). FA is partially supported by grant number 1UH2TR000963 (PIs: Akhlaghi and Leggio) from the National Center for Advancing Translational Sciences (NCATS), NIH.

Author contributions

MRL and BBA conceived and designed the study; KBS, MAH and XXD designed and validated the oxytocin assay for oxytocin; MRL and AC conducted the monkey study; MRL, FA, KBS and BBA analyzed the data; MRL, BBA, LL and KBS wrote the manuscript.

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Author notes

  1. L Leggio and B B Averbeck: These two authors contributed equally to this work.

Authors and Affiliations

  1. jointly supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and Intramural Research Program (IRP) of the National Institute of Drug Abuse (NIDA), NIH Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, Bethesda, MD, USA

    M R Lee & L Leggio

  2. NIH Section on Chemistry and Drug Metabolism, Clinical Pharmacology and Therapeutics Research Branch and Intramural Research Program (IRP) of the National Institute of Drug Abuse (NIDA), Bethesda, MD, USA

    K B Scheidweiler, X X Diao & M A Huestis

  3. Department of Biomedical and Pharmaceutical Sciences, Clinical Pharmacokinetics Research Laboratory, College of Pharmacy, University of Rhode Island, Kingston, RI, USA

    F Akhlaghi

  4. Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    A Cummins & B B Averbeck

  5. Department of Behavioral and Social Sciences, Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA

    L Leggio

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  1. M R Lee
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  2. K B Scheidweiler
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  4. F Akhlaghi
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Correspondence to M R Lee.

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Lee, M., Scheidweiler, K., Diao, X. et al. Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay. Mol Psychiatry 23, 115–122 (2018). https://doi.org/10.1038/mp.2017.27

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