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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)


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
Pages (from-to)710-720
Number of pages11
JournalMolecular Psychiatry
Issue number2
Publication statusPublished - 2021 Feb

ASJC Scopus subject areas

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


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