Functional and molecular changes in the nucleus accumbens of MK-801-sensitized rats

Emilia Lefevre, Helen Gooch, Peter Josh, Suzy Alexander, Darryl W. Eyles, Thomas H.J. Burne

Research output: Contribution to journalArticlepeer-review


Behavioural sensitization is a putative mechanism in the pathophysiology of drug addiction and neuropsychiatric disorders such as schizophrenia. In rodents, drug-induced behavioural sensitization has been described for several different drug classes. The N-methyl-d-aspartate receptor antagonist MK-801 can inhibit sensitization to other drugs of abuse. However, MK-801 also produces behavioural sensitization to its own hyperlocomotor inducing effects, suggesting that MK-801 sensitization has a distinctive mechanism of action. The aim of this study was to carry out a functional and molecular analysis of the nucleus accumbens (NAc) of adult male Sprague-Dawley rats sensitized to MK-801 (seven daily injections of 0.25 mg/kg, 5 days of withdrawal and subsequent 0.25 mg/kg challenge), or following acute MK-801 (0.25 mg/kg), or naive rats as controls. Locomotor activity was the primary measure of sensitization. Ex-vivo slice electrophysiology showed a decrease in the excitatory synaptic strength in the NAc of rats sensitized to MK-801 compared with acute MK-801 treatment or naive controls. An LC-MS/MS SWATH proteomics approach showed that proteins altered by MK-801 sensitization were predominantly related to functions including calcium and glutamate signalling, and mitochondrial dysfunction. These results shed some light on neural changes in the NAc after sensitization to MK-801. This model could prove useful for studying the role of N-methyl-d-aspartate receptors in the pathophysiology of drug addiction and schizophrenia.

Original languageEnglish (US)
Pages (from-to)383-395
Number of pages13
JournalBehavioural Pharmacology
Issue number5
StatePublished - Aug 1 2019

Bibliographical note

Funding Information:
Research reported in this publication was supported by the National Health and Medical Research Council (APP 1024239).

Publisher Copyright:
© 2018 Wolters Kluwer Health, Inc. All rights reserved.


  • MK-801
  • nucleus accumbens
  • proteomics
  • rat
  • sensitization


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