Neurochemical evidence for differential effects of acute and repeated oxytocin administration


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.

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We thank Drs. T. Kadowaki, T. Iwatsubo, and Y. Arakawa in the Project to Create Early-Stage and Exploratory Clinical Trial Centres for providing MRI scanning opportunities. A part of this study is the result of Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (23659558; 26670535 to HY), the Strategic Research Program for Brain Sciences of the Japan Agency for Medical Research and Development (to HY and MaKa), and the Center of Innovation Program of the Japan Science and Technology Agency (HY). HY had full access to all study data and takes responsibility for its integrity and the accuracy of the data analysis. We thank Richard Lipkin, PhD, from Edanz Group ( for editing a draft of this manuscript. A research grant from Takeda Science Foundation (to HB).

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Correspondence to Hidenori Yamasue.

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Benner, S., Aoki, Y., Watanabe, T. et al. Neurochemical evidence for differential effects of acute and repeated oxytocin administration. Mol Psychiatry (2018).

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