mGluR5-antagonist mediated reversal of elevated stereotyped, repetitive behaviors in the VPA model of autism

PLoS One. 2011;6(10):e26077. doi: 10.1371/journal.pone.0026077. Epub 2011 Oct 7.

Abstract

Autism spectrum disorders (ASD) are highly disabling developmental disorders with a population prevalence of 1-3%. Despite a strong genetic etiology, there are no current therapeutic options that target the core symptoms of ASD. Emerging evidence suggests that dysfunction of glutamatergic signaling, in particular through metabotropic glutamate receptor 5 (mGluR5) receptors, may contribute to phenotypic deficits and may be appropriate targets for pharmacologic intervention. This study assessed the therapeutic potential of 2-methyl-6-phenylethyl-pyrididine (MPEP), an mGluR5-receptor antagonist, on repetitive and anxiety-like behaviors in the valproic acid (VPA) mouse model of autism. Mice were exposed prenatally on day E13 to VPA and assessed for repetitive self-grooming and marble burying behaviors as adults. Anxiety-like behavior and locomotor activity were measured in an open-field. VPA-exposed mice displayed increased repetitive and anxiety-like behaviors, consistent with previously published results. Across both marble burying and self-grooming assays, MPEP significantly reduced repetitive behaviors in VPA-treated mice, but had no effect on locomotor activity. These results are consistent with emerging preclinical literature that mGluR5-antagonists may have therapeutic efficacy for core symptoms of autism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology
  • Anti-Anxiety Agents / therapeutic use
  • Autistic Disorder / chemically induced*
  • Autistic Disorder / drug therapy*
  • Autistic Disorder / physiopathology
  • Behavior, Animal / drug effects*
  • Disease Models, Animal
  • Female
  • Grooming / drug effects
  • Mice
  • Motor Activity / drug effects
  • Pregnancy
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Stereotyped Behavior / drug effects*
  • Valproic Acid / adverse effects*

Substances

  • Anti-Anxiety Agents
  • Grm5 protein, mouse
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Valproic Acid
  • 6-methyl-2-(phenylethynyl)pyridine