Neurochemical evidence for differential effects of acute and repeated oxytocin administration

Seico Benner, Yuta Aoki, Takamitsu Watanabe, Nozomi Endo, Osamu Abe, Miho Kuroda, Hitoshi Kuwabara, Yuki Kawakubo, Hidemasa Takao, Akira Kunimatsu, Kiyoto Kasai, Haruhiko Bito, Masaki Kakeyama, Hidenori Yamasue

    Research output: Contribution to journalArticle

    2 Citations (Scopus)

    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 1H-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.

    Original languageEnglish
    JournalMolecular Psychiatry
    DOIs
    Publication statusAccepted/In press - 2018 Jan 1

    Fingerprint

    Oxytocin
    Placebos
    Intranasal Administration
    Intraperitoneal Injections
    Inbred C57BL Mouse
    Cross-Over Studies
    Magnetic Resonance Spectroscopy
    Magnetic Resonance Imaging
    Clinical Trials

    ASJC Scopus subject areas

    • Molecular Biology
    • Psychiatry and Mental health
    • Cellular and Molecular Neuroscience

    Cite this

    Benner, S., Aoki, Y., Watanabe, T., Endo, N., Abe, O., Kuroda, M., ... Yamasue, H. (Accepted/In press). Neurochemical evidence for differential effects of acute and repeated oxytocin administration. Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0249-4

    Neurochemical evidence for differential effects of acute and repeated oxytocin administration. / Benner, Seico; Aoki, Yuta; Watanabe, Takamitsu; Endo, Nozomi; Abe, Osamu; Kuroda, Miho; Kuwabara, Hitoshi; Kawakubo, Yuki; Takao, Hidemasa; Kunimatsu, Akira; Kasai, Kiyoto; Bito, Haruhiko; Kakeyama, Masaki; Yamasue, Hidenori.

    In: Molecular Psychiatry, 01.01.2018.

    Research output: Contribution to journalArticle

    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 2018, 'Neurochemical evidence for differential effects of acute and repeated oxytocin administration', Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0249-4
    Benner, Seico ; Aoki, Yuta ; Watanabe, Takamitsu ; Endo, Nozomi ; Abe, Osamu ; Kuroda, Miho ; Kuwabara, Hitoshi ; Kawakubo, Yuki ; Takao, Hidemasa ; Kunimatsu, Akira ; Kasai, Kiyoto ; Bito, Haruhiko ; Kakeyama, Masaki ; Yamasue, Hidenori. / Neurochemical evidence for differential effects of acute and repeated oxytocin administration. In: Molecular Psychiatry. 2018.
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    AU - Kuroda, Miho

    AU - Kuwabara, Hitoshi

    AU - Kawakubo, Yuki

    AU - Takao, Hidemasa

    AU - Kunimatsu, Akira

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