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

Lefevre, Emiliaa,*; Gooch, Helena,*; Josh, Petera; Alexander, Suzya; Eyles, Darryl W.a,b; Burne, Thomas H.J.a,b

doi: 10.1097/FBP.0000000000000447

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.

aQueensland Brain Institute, The University of Queensland

bQueensland Centre for Mental Health Research, Wacol, Queensland, Australia

* Emilia Lefevre and Helen Gooch contributed equally to the writing of this article.

Correspondence to Thomas H.J. Burne, B.Rur.Sc (Hons I), PhD, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia E-mail:

Received June 13, 2018

Accepted September 12, 2018

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