Biomol Ther  
Effects of Intraperitoneal N-methyl-D-aspartate (NMDA) Administration on Nociceptive/Repetitive Behaviors in Juvenile Mice
Seonmin Kim1, Do Gyeong Kim1, Edson luck Gonzales1, Darine Froy N. Mabunga1, Dongpil Shin1, Se Jin Jeon1, Chan Young Shin1, TaeJin Ahn2,* and Kyoung Ja Kwon1,*
1Department of Neuroscience, School of Medicine, Konkuk University, Seoul 05029,
2Life Science, Handong Global University, Pohang 37554, Republic of Korea
E-mail: kjjasmine@hanmail.net (Kwon KJ), taejin.ahn@handong.edu (Ahn TJ)
Tel: +82-2-454-5630 (Kwon KJ), +82-54-260-1360 (Ahn TJ)
Fax: +82-2-2030-7899 (Kwon KJ), +82-54-260-1305 (Ahn TJ)
Received: December 5, 2018; Revised: December 11, 2018; Accepted: December 17, 2018; Published online: December 24, 2018.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Dysregulation of excitatory neurotransmission has been implicated in the pathogenesis of neuropsychiatric disorders. Pharmacological inhibition of N-methyl-D-aspartate receptors is widely used to model neurobehavioral pathologies and underlying mechanisms. There is ample evidence that overstimulation of N-methyl-D-aspartate-dependent neurotransmission may induce neurobehavioral abnormalities, such as repetitive behaviors and hypersensitization to nociception and cognitive disruption, pharmacological modeling using N-methyl-D-aspartate has been limited due to the induction of neurotoxicity and blood brain barrier breakdown, especially in young animals. In this study, we examined the effects of intraperitoneal N-methyl-D-aspartate-administration on nociceptive and repetitive behaviors in ICR mice. Intraperitoneal injection of N-methyl-D-aspartate induced repetitive grooming and tail biting/licking behaviors in a dose- and age-dependent manner. Nociceptive and repetitive behaviors were more prominent in juvenile mice than adult mice. We did not observe extensive blood brain barrier breakdown or neuronal cell death after peritoneal injection of N-methyl-D-aspartate, indicating limited neurotoxic effects despite a significant increase in N-methyl-D-aspartate concentration in the cerebrospinal fluid. These findings suggest that the observed behavioral changes were not mediated by general N-methyl-D-aspartate toxicity. In the hot plate test, we found that the latency of paw licking and jumping decreased in the N-methyl-D-aspartate-exposed mice especially in the 75 mg/kg group, suggesting increased nociceptive sensitivity in N-methyl-D-aspartate-treated animals. Repetitive behaviors and increased pain sensitivity are often comorbid in psychiatric disorders (e.g., autism spectrum disorder). Therefore, the behavioral characteristics of intraperitoneal N-methyl-D-aspartate-administered mice described herein may be valuable for studying the mechanisms underlying relevant disorders and screening candidate therapeutic molecules.
Keywords: Stereotypy, Tail Licking/Biting, Nociception, Repetitive Behavior, E/I Imbalance


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