Modulation of Behavioral Phenotypes by a Muscarinic M1 Antagonist in a Mouse Model of Fragile X Syndrome

Psychopharmacology (Berl). 2011 Sep;217(1):143-51. doi: 10.1007/s00213-011-2276-6. Epub 2011 Apr 13.

Abstract

Rationale: Muscarinic acetylcholine receptors (mAChR) are G protein-coupled receptors, widely expressed in the CNS. Electrophysiological and molecular studies have provided evidence for overactive M1 receptor signaling in the fragile X knockout (Fmr1 KO) mouse model, suggesting the involvement of the M1 receptors in fragile X syndrome. Overactive signaling through the M1 receptor has been hypothesized to contribute to the phenotypes seen in fragile X mice.

Objective: We investigated the modulation of behavioral responses in the Fmr1 KO animals by reducing the activity through the muscarinic M1 receptor using the pharmacological agent dicyclomine, an M1 antagonist.

Methods: The behavioral assays used to investigate the pharmacological effects include marble burying (perseverative behavior), open-field exploration (activity), passive avoidance (learning and memory), prepulse inhibition (sensorimotor gating), and audiogenic seizures.

Results: Data from the marble-burying assay suggests that treatment with dicyclomine results in a decrease in the number of marbles buried in the wild-type and in the KO animals. To examine the possibility of drug-induced sedation, overall activity was measured in an open-field chamber. Dicyclomine only increases activity at a dose of 20 mg/kg in the wild-type mice but did not affect exploration in the KO animals. Lastly, we observed that dicyclomine causes a significant decrease in the percentage of audiogenic seizures in the Fmr1 KO animals.

Conclusion: Our findings suggest that pharmacologically reducing the activity through the mAChR M1 alters select behavioral responses in the Fmr1 KO mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Dicyclomine / therapeutic use*
  • Disease Models, Animal
  • Epilepsy, Reflex / genetics
  • Epilepsy, Reflex / physiopathology
  • Epilepsy, Reflex / prevention & control
  • Exploratory Behavior / drug effects
  • Female
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Syndrome / complications
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / physiopathology*
  • Male
  • Mice
  • Mice, Knockout
  • Motor Activity / drug effects
  • Muscarinic Antagonists / therapeutic use*
  • Receptor, Muscarinic M1 / antagonists & inhibitors*
  • Reflex, Startle / drug effects

Substances

  • Fmr1 protein, mouse
  • Muscarinic Antagonists
  • Receptor, Muscarinic M1
  • Fragile X Mental Retardation Protein
  • Dicyclomine