CSF and blood oxytocin concentration changes following intranasal delivery in macaque
Open accessAbstract
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.
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In macaques given 48 IU intranasal oxytocin, CSF oxytocin rose from about 35 to about 90 pg/ml at 40 minutes; assuming a 40 ml CSF volume, the additional amount was 2.2 ng, or 0.002% of the dose.
“Dal Monte et al. gave 48IU oxytocin (~10µg/kg body weight) intranasally to macaques, using either a spray or nebuliser (23).These increased CSF oxytocin from ~35pg/ml to ~90pg/ml after 40min.On the (very) conservative assumption that the CSF/ECF volume in the macaque is 40ml, then the additional content at this time is 2.2ng, 0.002% of the administered dose.”
From Intranasal Oxytocin: Myths and Delusions (2016) · cites this paper as [23]
The Methods report 48 IU intranasal oxytocin given to macaques by spray or nebulizer, and the Results report a significant CSF increase at 40 minutes. Our copy does not state the approximate 35-to-90 pg/ml values; Figure 1’s caption identifies the measurements but gives no numbers. The 40 ml assumption and resulting 2.2 ng and 0.002% calculations are presented as the citing authors’ own, not as findings of Dal Monte et al. (Section passages have no page numbers in our copy.) (LLM, conf=0.82)
Experimental — accuracy not yet measuredAnimal studies in rodents and nonhuman primates have shown central elevations of OT concentration 30 min after intranasal administration.
“Behavioral testing began 30 min after each treatment, given that animal studies in both rodents (53) and nonhuman primate (54, 55) have shown central elevations of OT concentration after 30 min from intranasal administration.”
From Oxytocin under opioid antagonism leads to supralinear enhancement of social attention (2017) · cites this paper as [55]
The intranasal dose administered in the present study has been associated with changes in central function in humans, and similar or smaller doses of oxytocin or vasopressin have been associated with elevations in peptide levels in the cerebrospinal fluid in humans or macaques of no more than approximately 55 pg/ml or up to 0.005% of the administered dose.
“The intranasal dose administered in the present study has been associated with changes in central function in humans 58, and similar or smaller doses of oxytocin or vasopressin (24–48 IU for oxytocin; 40–80 IU for vasopressin) have been associated with elevations in peptide levels in the cerebrospinnal fluid in humans or macaques of no more than approximately 55 pg/ml in actual levels 70, 71, 72,”
From The Analgesic Effect of Oxytocin in Humans: A Double‐Blind, Placebo‐Controlled Cross‐Over Study Using Laser‐Evoked Potentials (2016) · cites this paper as [74]
In monkeys, intranasal oxytocin or oxytocin intake via a nebulizer at 25 or 48 IU increased cerebrospinal fluid oxytocin concentration compared with placebo.
“Also, in monkeys, IN-OT or OT intake via a nebulizer (25 or 48 IU) increased OT CSF concentration compared to placebo (Chang et al. 2012; Dal Monte et al. 2014; Modi et al. 2014).”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as Dal Monte et al. 2014
There is considerable debate regarding whether peripheral levels of oxytocin reflect central expression in humans, with mixed evidence reported to date.
“Lastly, there exists considerable debate regarding whether peripheral levels of oxytocin reflect central expression in humans, with mixed evidence reported to date.26,27”
From Beyond the hype and hope: critical considerations for intranasal oxytocin research in autism spectrum disorder (2017) · cites this paper as [27]
Only a small amount of intranasally administered oxytocin reaches the brain.
“It is estimated that only a small amount of intranasally administered oxytocin reaches the brain.33, 34, 46, 47”
From Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial (2016) · cites this paper as [47]
The immediate influence of intranasal oxytocin on psychopathology and brain function is supported by primate studies showing intranasal oxytocin reaches cerebrospinal fluid.
“The here-observed immediate influence of intranasal oxytocin on psychopathology and hence on brain function is supported by primate studies showing that intranasal oxytocin, such as other intranasally administered anxiolytic neuropeptides like NPS [45], are able to reach the cerebrospinal fluid [46, 47] and thus, assumingly, also the brain.”
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References 47 · Cited by 177
- Authors
- Dal Monte, O., Noble, P. L., Turchi, J., Cummins, A., & Averbeck, B. B.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Averbeck, Bruno B.
- ORCID
- Averbeck, Bruno B.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-08-18
- Volume
- 9
- Issue
- 8
- Pages
- e103677
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4136720
- OpenAlex
- W2125447065
- Cited by
- 177
- References
- 47
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 6 · 2023: 4 · 2022: 6 · 2021: 14 · 2020: 9 · 2019: 22 · 2018: 31 · 2017: 28 · 2016: 28 · 2015: 18
- FWCI
- 36.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- U.S. Department of Health and Human Services
- National Institutes of Health
- National Institute of Mental Health
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Keywords
- oxytocin, intranasal drug delivery, cerebrospinal fluid, nebulizer, nasal spray, macaque, nonhuman primate model, social cognition, schizophrenia, autism spectrum disorder
- MeSH terms
- Administration, Intranasal, Animals, Blood-Brain Barrier, Macaca mulatta, Male, Oxytocics, Oxytocin, Tissue Distribution
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