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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References
Ju G, Liu S, Tao J . Projections from the hypothalamus and its adjacent areas to the posterior pituitary in the rat. Neuroscience 1986; 19: 803–828.
Knobloch HS, Charlet A, Hoffmann LC, Eliava M, Khrulev S, Cetin AH et al. Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron 2012; 73: 553–566.
Stoop R . Neuromodulation by oxytocin and vasopressin in the central nervous system as a basis for their rapid behavioral effects. Curr Opin Neurobiol 2014; 29: 187–193.
Meyer-Lindenberg A, Domes G, Kirsch P, Heinrichs M . Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat Rev Neurosci 2011; 12: 524–538.
Macdonald K, Macdonald TM . The peptide that binds: a systematic review of oxytocin and its prosocial effects in humans. Harv Rev Psychiatry 2010; 18: 1–21.
Wei D, Lee D, Cox CD, Karsten CA, Penagarikano O, Geschwind DH et al. Endocannabinoid signaling mediates oxytocin-driven social reward. Proc Natl Acad Sci USA 2015; 112: 14084–14089.
Mottolese R, Redoute J, Costes N, Le Bars D, Sirigu A . Switching brain serotonin with oxytocin. Proc Natl Acad Sci USA 2014; 111: 8637–8642.
MacDonald E, Dadds MR, Brennan JL, Williams K, Levy F, Cauchi AJ . A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research. Psychoneuroendocrinology 2011; 36: 1114–1126.
Vyas TK, Shahiwala A, Marathe S, Misra A . Intranasal drug delivery for brain targeting. Curr Drug Deliv 2005; 2: 165–175.
Kozlovskaya L, Abou-Kaoud M, Stepensky D . Quantitative analysis of drug delivery to the brain via nasal route. J Control Release 2014; 189: 133–140.
Mens WB, Witter A, van Wimersma Greidanus TB . Penetration of neurohypophyseal hormones from plasma into cerebrospinal fluid (CSF): half-times of disappearance of these neuropeptides from CSF. Brain Res 1983; 262: 143–149.
Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL . Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 2002; 5: 514–516.
Chang SW, Barter JW, Ebitz RB, Watson KK, Platt ML . Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta. Proc Natl Acad Sci USA 2012; 109: 959–964.
Dal Monte O, Noble PL, Turchi J, Cummins A, Averbeck BB . CSF and blood oxytocin concentration changes following intranasal delivery in macaque. PLoS ONE 2014; 9: e103677.
Freeman SM, Samineni S, Allen PC, Stockinger D, Bales KL, Hwa GG et al. Plasma and CSF oxytocin levels after intranasal and intravenous oxytocin in awake macaques. Psychoneuroendocrinology 2016; 66: 185–194.
Modi ME, Connor-Stroud F, Landgraf R, Young LJ, Parr LA . Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques. Psychoneuroendocrinology 2014; 45: 49–57.
Neumann ID, Maloumby R, Beiderbeck DI, Lukas M, Landgraf R . Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology 2013; 38: 1985–1993.
Striepens N, Kendrick KM, Hanking V, Landgraf R, Wullner U, Maier W et al. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci Rep 2013; 3: 3440.
Ermisch A, Ruhle HJ, Landgraf R, Hess J . Blood-brain barrier and peptides. J Cereb Blood Flow Metab 1985; 5: 350–357.
Carson DS, Hunt GE, Guastella AJ, Barber L, Cornish JL, Arnold JC et al. Systemically administered oxytocin decreases methamphetamine activation of the subthalamic nucleus and accumbens core and stimulates oxytocinergic neurons in the hypothalamus. Addict Biol 2010; 15: 448–463.
Maejima Y, Rita RS, Santoso P, Aoyama M, Hiraoka Y, Nishimori K et al. Nasal oxytocin administration reduces food intake without affecting locomotor activity and glycemia with c-Fos induction in limited brain areas. Neuroendocrinology 2015; 101: 35–44.
Rutigliano G, Rocchetti M, Paloyelis Y, Gilleen J, Sardella A, Cappucciati M et al. Peripheral oxytocin and vasopressin: biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis. Psychiatry Res 2016; 241: 207–220.
Ludwig M, Leng G . Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci 2006; 7: 126–136.
Szeto A, McCabe PM, Nation DA, Tabak BA, Rossetti MA, McCullough ME et al. Evaluation of enzyme immunoassay and radioimmunoassay methods for the measurement of plasma oxytocin. Psychosom Med 2011; 73: 393–400.
Thorne RG, Pronk GJ, Padmanabhan V, Frey WH 2nd . Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 2004; 127: 481–496.
Fabian M, Forsling ML, Jones JJ, Lee J . The release, clearance and plasma protein binding of oxytocin in the anaesthetized rat. J Endocrinol 1969; 43: 175–189.
Wigton R, Radua J, Allen P, Averbeck B, Meyer-Lindenberg A, McGuire P et al. Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies. J Psychiatry Neurosci 2015; 40: E1–E22.
Iwasaki Y, Maejima Y, Suyama S, Yoshida M, Arai T, Katsurada K et al. Peripheral oxytocin activates vagal afferent neurons to suppress feeding in normal and leptin-resistant mice: a route for ameliorating hyperphagia and obesity. Am J Physiol Regul Integr Comp Physiol 2015; 308: R360–R369.
Leake RD, Weitzman RE, Fisher DA . Pharmacokinetics of oxytocin in the human subject. Obstet Gynecol 1980; 56: 701–704.
Lee MR, Rohn MC, Tanda G, Leggio L . Targeting the oxytocin system to treat addictive disorders: rationale and progress to date. CNS Drugs 2016; 30: 109–123.
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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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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DOI: https://doi.org/10.1038/mp.2017.27
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