Effect of the glucocorticoid receptor antagonist RU486 on MK-801 induced behavioural sensitization

Emilia M. Lefevre, Gregory A. Medley, Timothy Reeks, Suzy Alexander, Thomas H.J. Burne, Darryl W. Eyles

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Stress is known to modulate sensitisation to repeated psychostimulant exposure. However, there is no direct evidence linking glucocorticoids and sensitisation achieved by repeated administration of the NMDA receptor antagonist MK-801. We tested the hypothesis that coadministration of RU486, a glucocorticoid receptor (GR) antagonist, prior to repeated daily MK-801 injections would block the expression of locomotor sensitisation due to its dual effects on corticosterone and dopamine. We employed a repeated MK-801 administration locomotor sensitisation paradigm in male Sprague Dawley rats. RU486 or a dimethyl sulfoxide (DMSO) vehicle was co-Administered with MK-801 or saline during the induction phase. Subsequent to withdrawal, rats were challenged with MK-801 alone to test for the expression of sensitisation. In a separate cohort of rats, plasma corticosterone levels were quantified from blood samples taken on the 1st, 4th and 7th day of induction and at expression. One day after challenge, nucleus accumbens tissue levels of dopamine and its metabolites DOPAC and HVA were measured. During the induction phase, RU486 progressively enhanced locomotor sensitisation to MK-801. RU486 and MK-801 both showed stimulatory effects on corticosterone levels and this was further augmented when given in combination. Contrary to our hypothesis, RU486 did not block the expression of locomotor sensitisation to MK-801 and actually increased levels of dopamine, DOPAC and HVA in nucleus accumbens tissue. Our results showed that RU486 has augmentative rather than inhibitory effects on MK-801-induced sensitisation. This study indicates a divergent role for glucocorticoids in sensitisation to MK-801 compared to sensitisation with other psychostimulants.

Original languageEnglish (US)
Article numbere0176156
JournalPloS one
Volume12
Issue number4
DOIs
StatePublished - Apr 2017

Bibliographical note

Funding Information:
This work was supported by NHMRC project grant 1024239.

Publisher Copyright:
© 2017 Lefevre et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Fingerprint

Dive into the research topics of 'Effect of the glucocorticoid receptor antagonist RU486 on MK-801 induced behavioural sensitization'. Together they form a unique fingerprint.

Cite this