Psychopharmacology

, 217:143

Modulation of behavioral phenotypes by a muscarinic M1 antagonist in a mouse model of fragile X syndrome

  • Surabi Veeraragavan
  • Nghiem Bui
  • Jennie R. Perkins
  • Lisa A. Yuva-Paylor
  • Randall L. Carpenter
  • Richard Paylor
Original Investigation

DOI: 10.1007/s00213-011-2276-6

Cite this article as:
Veeraragavan, S., Bui, N., Perkins, J.R. et al. Psychopharmacology (2011) 217: 143. doi:10.1007/s00213-011-2276-6

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.

Keywords

Fragile X syndrome Muscarinic Dicyclomine Behavior Cholinergic M1 antagonist Modulation Audiogenic seizures Marble burying Passive avoidance 

Abbreviations

mAChR

Muscarinic acetylcholine receptor

WT

Wild type

KO

Knockout

MB

Marble burying

OFA

Open-field activity

PPI

Prepulse inhibition

PA

Passive avoidance

AGS

Audiogenic seizures

mg

Milligram

kg

Kilogram

s

Second

cm

Centimeter

dB

Decibel

ANOVA

Analysis of variance

SEM

Standard error of the mean

FXS

Fragile X syndrome

FMRP

Fragile X mental retardation protein

mGluR

Metabotropic glutamate receptors

LTD

Long-term depression

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Surabi Veeraragavan
    • 1
  • Nghiem Bui
    • 1
  • Jennie R. Perkins
    • 1
  • Lisa A. Yuva-Paylor
    • 1
  • Randall L. Carpenter
    • 3
  • Richard Paylor
    • 1
    • 2
  1. 1.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  2. 2.Department of NeuroscienceBaylor College of MedicineHoustonUSA
  3. 3.Seaside TherapeuticsCambridgeUSA