Mouse model of OPRM1 (A118G) polymorphism has altered hippocampal function

Stephen D. Mague, Russell G. Port, Michael E. McMullen, Greg C. Carlson, Jill R. Turner

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

A single nucleotide polymorphism (SNP) in the human μ-opioid receptor gene (OPRM1 A118G) has been widely studied for its association in a variety of drug addiction and pain sensitivity phenotypes; however, the extent of these adaptations and the mechanisms underlying these associations remain elusive. To clarify the functional mechanisms linking the OPRM1 A118G SNP to altered phenotypes, we used a mouse model possessing the equivalent nucleotide/amino acid substitution in the Oprm1 gene. In order to investigate the impact of this SNP on circuit function, we used voltage-sensitive dye imaging in hippocampal slices and in vivo electroencephalogram recordings of the hippocampus following MOPR activation. As the hippocampus contains excitatory pyramidal cells whose activity is highly regulated by a dense network of inhibitory neurons, it serves as an ideal structure to evaluate how putative receptor function abnormalities may influence circuit activity. We found that MOPR activation increased excitatory responses in wild-type animals, an effect that was significantly reduced in animals possessing the Oprm1 SNP. Furthermore, in order to assess the in vivo effects of this SNP during MOPR activation, EEG recordings of hippocampal activity following morphine administration corroborated a loss-of-function phenotype. In conclusion, as these mice have been shown to have similar MOPR expression in the hippocampus between genotypes, these data suggest that the MOPR A118G SNP results in a loss of receptor function.

Original languageEnglish
Pages (from-to)426-435
Number of pages10
JournalNeuropharmacology
Volume97
DOIs
StatePublished - Aug 3 2015

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grants R00-DA-032681 (to J.R.T.) and T32-DA-007241–15 (to S.D.M.) from the National Institute on Drug Abuse. We would like to thank Dr. Julie A. Blendy for generously providing the A112G MOPR mice used in these experiments and Ms. Mary McMullen for assistance with statistical analysis. We would like to thank Dr. Luyi Zhou and Ms. Miranda Fisher for critical review of the manuscript.

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved © 2015 Elsevier Ltd. All rights reserved.

Keywords

  • A112G
  • A118G
  • Genotype
  • Hippocampus
  • Mice
  • Mu-opioid receptor
  • N40D
  • OPRM1
  • Sex
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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