Effect of the glucocorticoid receptor antagonist RU486 on MK-801 induced behavioural sensitisation
Emilia M. Lefevre, Gregory Medley, Timothy Reeks, Suzy Alexander, Thomas H.j. Burne, Darryl W. Eyles
PLoS ONE April 21, 2017 Peer reviewed DOI: 10.1371/journal.pone.0176156 via OpenAlex
Summary
Co-administration of RU486, a glucocorticoid receptor antagonist, with MK-801 increased locomotor sensitisation in male Sprague Dawley rats, contrary to expectations that it would block this effect. RU486 enhanced corticosterone levels and elevated dopamine, DOPAC, and HVA in the nucleus accumbens. These findings suggest that glucocorticoids play a different role in sensitisation to MK-801 compared to other psychostimulants.
Study at a glance
| Design | experimental study |
|---|---|
| Population | male Sprague Dawley rats |
| Key finding | RU486 enhanced rather than blocked locomotor sensitisation to MK-801. |
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 co-administration 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.