Biomol Ther.  2019 Feb;27(2):168-177. 10.4062/biomolther.2018.230.

Effects of Intraperitoneal N-methyl-D-aspartate (NMDA) Administration on Nociceptive/Repetitive Behaviors in Juvenile Mice

• Kim S
• Kim DG
• Gonzales E
• Mabunga DF
• Shin D
• Jeon SJ
• Shin CY
• Ahn T
• Kwon KJ

• KMID: 2442008
• DOI: http://doi.org/10.4062/biomolther.2018.230

Abstract

Dysregulation of excitatory neurotransmission has been implicated in the pathogenesis of neuropsychiatric disorders. Pharmacological inhibition of N-methyl-D-aspartate (NMDA) receptors is widely used to model neurobehavioral pathologies and underlying mechanisms. There is ample evidence that overstimulation of NMDA-dependent neurotransmission may induce neurobehavioral abnormalities, such as repetitive behaviors and hypersensitization to nociception and cognitive disruption, pharmacological modeling using NMDA 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 NMDA-administration on nociceptive and repetitive behaviors in ICR mice. Intraperitoneal injection of NMDA 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 NMDA, indicating limited neurotoxic effects despite a significant increase in NMDA concentration in the cerebrospinal fluid. These findings suggest that the observed behavioral changes were not mediated by general NMDA toxicity. In the hot plate test, we found that the latency of paw licking and jumping decreased in the NMDA-exposed mice especially in the 75 mg/kg group, suggesting increased nociceptive sensitivity in NMDA-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 NMDA-administered mice described herein may be valuable for studying the mechanisms underlying relevant disorders and screening candidate therapeutic molecules.

Keyword

Stereotypy; Tail Licking/Biting; Nociception; Repetitive Behavior; E/I Imbalance

MeSH Terms

Adult
Animals
Autistic Disorder
Blood-Brain Barrier
Cell Death
Cerebrospinal Fluid
Grooming
Humans
Injections, Intraperitoneal
Mass Screening
Mice*
Mice, Inbred ICR
N-Methylaspartate*
Neurons
Nociception
Pathology
Synaptic Transmission
Tail
N-Methylaspartate