title: 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.
authors.affiliation: NIH Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, 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), Bethesda, MD, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: K B
authors.initials: KB
authors.lastname: Scheidweiler
authors.affiliation: 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.
authors.forename: X X
authors.initials: XX
authors.lastname: Diao
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, Clinical Pharmacokinetics Research Laboratory, College of Pharmacy, University of Rhode Island, Kingston, RI, USA.
authors.forename: F
authors.initials: F
authors.lastname: Akhlaghi
authors.affiliation: Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Cummins
authors.affiliation: 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.
authors.forename: M A
authors.initials: MA
authors.lastname: Huestis
authors.affiliation: NIH Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, 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), Bethesda, MD, USA.|Department of Behavioral and Social Sciences, Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Leggio
authors.affiliation: Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: B B
authors.initials: BB
authors.lastname: Averbeck
mesh_terms: D000281:Administration, Intranasal / Q000379:methods*; D061605:Administration, Intravenous / Q000379:methods*; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D000078331:Correlation of Data; D008253:Macaca mulatta; D008297:Male; D010121:Oxytocin / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D010121:Oxytocin