Neurochemical evidence for differential effects of acute and repeated oxytocin administration

• Published in: Molecular psychiatry Vol. 26; no. 2; pp. 710 - 720
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2021; Nature Publishing Group
• Subjects: 38/39; 38/90; 59/57; 631/378; 692/699/476/1373; Administration, Intranasal; Animals; Autism; Autism Spectrum Disorder - drug therapy; Behavior; Behavioral Sciences; Biological Psychology; Brain research; Clinical trials; Comorbidity; Dosage and administration; Double-Blind Method; Drug therapy; Functional magnetic resonance imaging; Glutamatergic transmission; Glutamic acid receptors; Glutamine; Humans; Magnetic Resonance Imaging; Magnetic resonance spectroscopy; Male; Medicine; Medicine & Public Health; Metabolites; Mice; Mice, Inbred C57BL; N-Acetylaspartate; N-Methyl-D-aspartic acid receptors; Neurobiology; Neurochemistry; Neurosciences; Oxytocin; Oxytocin - therapeutic use; Pervasive developmental disorders; Pharmacotherapy; Physiological aspects; Placebos; Psychiatry; Spectrum analysis; Transcription; Japan
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-018-0249-4

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.