Neurochemical evidence for differential effects of acute and repeated oxytocin administration
Abstract
A discrepancy in oxytocin's behavioral effects between acute and repeated administrations indicates distinct underlying neurobiological mechanisms. The current study employed a combination of human clinical trial and animal study to compare neurochemical changes induced by acute and repeated oxytocin administrations. Human study analyzed medial prefrontal metabolite levels by using 1 H-magnetic resonance spectroscopy, a secondary outcome in our randomized, double-blind, placebo-controlled crossover trial of 6 weeks intranasal administrations of oxytocin (48 IU/day) and placebo within-subject design in 17 psychotropic-free high-functioning men with autism spectrum disorder. Medial prefrontal transcript expression levels were analyzed in adult male C57BL/6J mice after intraperitoneal injection of oxytocin or saline either once (200 ng/100 μL/mouse, n = 12) or for 14 consecutive days (200 ng/100 μL/mouse/day, n = 16). As the results, repeated administration of oxytocin significantly decreased the medial prefrontal N-acetylaspartate (NAA; p = 0.043) and glutamate-glutamine levels (Glx; p = 0.001), unlike the acute oxytocin. The decreases were inversely and specifically associated (r = 0.680, p = 0.004 for NAA; r = 0.491, p = 0.053 for Glx) with oxytocin-induced improvements of medial prefrontal functional MRI activity during a social judgment task not with changes during placebo administrations. In wild-type mice, we found that repeated oxytocin administration reduced medial frontal transcript expression of N-methyl-D-aspartate receptor type 2B (p = 0.018), unlike the acute oxytocin, which instead changed the transcript expression associated with oxytocin (p = 0.0004) and neural activity (p = 0.0002). The present findings suggest that the unique sensitivity of the glutamatergic system to repeated oxytocin administration may explain the differential behavioral effects of oxytocin between acute and repeated administration.
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There is uncertainty regarding absorption, brain penetration, and time course of effects with intranasal oxytocin.
“There is uncertainty regarding absorption, brain penetration, and time course of effects with intranasal oxytocin35,36 that may be amplified by differences among specific preparations of intranasal oxytocin.”
From Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder (2021) · cites this paper as [36]
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Gondi, C. S., Gnanamony, M., Gondi, T. P., Nersesyan, L., & Demirkhanyan, L. H. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48040417
- Authors
- Benner, S., Aoki, Y., Watanabe, T., Endo, N., Abe, O., Kuroda, M., Kuwabara, H., Kawakubo, Y., Takao, H., Kunimatsu, A., Kasai, K., Bito, H., Kakeyama, M., & Yamasue, H.
- Affiliations
- The University of Tokyo (JP)
- University College London (GB)
- Waseda University (JP)
- Hamamatsu University (JP)
- Corresponding author
- Yamasue, Hidenori
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2018-09-27
- Volume
- 26
- Issue
- 2
- Pages
- 710-720
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2893539678
- Cited by
- 40
- References
- 45
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 5 · 2021: 12 · 2020: 4 · 2019: 3 · 2018: 1
- FWCI
- 6.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23659558; 26670535)
- Japan Agency for Medical Research and Development (Strategic Research Program for Brain Sciences)
- Japan Science and Technology Agency (Center of Innovation Program)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- oxytocin, medial prefrontal cortex, N-acetylaspartate, glutamate/glutamine, glutamatergic system, NMDA receptor NR2B, social judgment, autism spectrum disorder, intranasal oxytocin, neurochemical changes
- MeSH terms
- Autism Spectrum Disorder, Administration, Intranasal, Animals, Double-Blind Method, Humans, Magnetic Resonance Imaging, Male, Mice, Inbred C57BL, Oxytocin, Mice
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