Mifepristone treatment affects the response to repeated amphetamine injections, but does not attenuate the expression of sensitization

Veen, Rixt van der; Boshuizen, Margit; Kloet, E. Ronald de

doi:10.1007/s00213-013-3176-8

Cited by 7 publications

(10 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on previous studies demonstrating a role for glucocorticoids in behavioural sensitisation to other psychostimulants, including cocaine [30], amphetamine [16], and ethanol [18], it was hypothesised that the co-administration of the GR antagonist would block the development of MK-801 sensitisation. The present results did not support this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

“…For instance it has been shown that adrenalectomy or the co-administration of the GR antagonist RU486 can block the induction of behavioural sensitisation to drugs of abuse [16–19]. However, once sensitisation is established, adrenalectomy past the induction phase has no effect on the expression of behavioural sensitisation [17, 19].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Fourth, repeated daily administration for 5 days up to three weeks revealed an unexpected apparent GR agonism of MIF and blocked basal and stress-induced HPA-axis activity in rodents (Havel et al 1996 ; Wulsin et al 2010 ; van der Veen et al 2013 ). Similar GR agonism rather than antagonism was noted with the novel selective GR modulators C-108297, C-125281, and the GR modulator/MR antagonist C-118335 (Solomon et al 2014 ; Nguyen et al 2017 ; Kroon et al 2018 ; Van den Heuvel et al 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Resetting the Stress System with a Mifepristone Challenge

et al. 2018

Self Cite

View full text Add to dashboard Cite

Psychotic depression is characterized by elevated circulating cortisol, and high daily doses of the glucocorticoid/progesterone antagonist mifepristone for 1 week are required for significant improvement. Using a rodent model, we find that such high doses of mifepristone are needed because the antagonist is rapidly degraded and poorly penetrates the blood-brain barrier, but seems to facilitate the entry of cortisol. We also report that in male C57BL/6J mice, after a 7-day treatment with a high dose of mifepristone, basal blood corticosterone levels were similar to that of vehicle controls. This is surprising because after the first mifepristone challenge, corticosterone remained elevated for about 16 h, and then decreased towards vehicle control levels at 24 h. At that time, stress-induced corticosterone levels of the 1xMIF were sevenfold higher than the 7xMIF group, the latter response being twofold lower than controls. The 1xMIF mice showed behavioral hyperactivity during exploration of the circular hole board, while the 7xMIF mice rather engaged in serial search patterns. To explain this rapid reset of corticosterone secretion upon recurrent mifepristone administration, we suggest the following: (i) A rebound glucocorticoid feedback after cessation of mifepristone treatment. (ii) Glucocorticoid agonism in transrepression and recruitment of cell-specific coregulator cocktails. (iii) A more prominent role of brain MR function in control of stress circuit activity. An overview table of neuroendocrine MIF effects is provided. The data are of interest for understanding the mechanistic underpinning of stress system reset as treatment strategy for stress-related diseases.

show abstract

“…A role for these receptors has been demonstrated during the induction phase of drug-induced sensitisation. For instance, coadministration of GR or MR antagonists during the induction phase has been found to inhibit sensitisation to cocaine, amphetamine, morphine and ethanol (Prasad et al, 1996, Przegalinski et al, 2000, Roberts et al, 1995, van der Veen et al, 2013. In support of a role for the GR in psychostimulant sensitisation, mice with selective GR ablations show a blunted behavioural sensitisation to cocaine (Deroche-Gamonet et al, 2003).…”

Section: Psychostimulant Sensitisation and Stressmentioning

confidence: 98%

“…For instance it has been shown that adrenalectomy or the co-administration of the GR antagonist RU486 can block the induction of behavioural sensitisation to drugs of abuse (Prasad et al, 1996, Przegalinski et al, 2000, Roberts et al, 1995, van der Veen et al, 2013. However, once sensitisation is established, adrenalectomy past the induction phase has no effect on the expression of behavioural sensitisation (Prasad et al, 1996, Przegalinski et al, 2000.…”

Section: Chapter 4 Role Of Glucocorticoids In Mk-801 Sensitisation 4mentioning

confidence: 99%

Neural mechanisms of MK-801 induced sensitisation

Lefevre¹

View full text Add to dashboard Cite

Behavioural sensitisation describes the progressive and enduring augmentation of a drug-induced response that develops with repeated exposure. Sensitisation is a putative mechanism in the pathophysiology of drug addiction and neuropsychiatric disorders such as schizophrenia. In rodents, drug-induced behavioural sensitisation has been described for several different drug classes. The neural mechanisms underpinning behavioural sensitisation to most drugs of abuse share similarities, such as NMDA receptor (NMDAR) activation, although not all use the same mechanism of action.The NMDAR antagonist MK-801 can inhibit sensitisation to other drugs of abuse. However, MK-801 also produces behavioural sensitisation to its own hyperlocomotor inducing effects, suggesting that MK-801 sensitisation has a distinctive mechanism of action.The overall aim of my thesis was to investigate the neural mechanisms of behavioural sensitisation to MK-801 in rats. First, I established the effect of drug dose, environmental context, length of withdrawal period and rat strain on the ability of repeated intermittent MK-801 administration to induce behavioural sensitisation. MK-801-induced sensitisation was shown to be dependent on the dose of MK-801, length of withdrawal period and the rat strain. Sensitisation however was not modulated by the environmental context in which MK-801 administration occurred.In the established sensitisation paradigm, a functional and molecular analysis of the nucleus accumbens of rats sensitised to MK-801 was undertaken. Ex vivo slice electrophysiology revealed a decrease in the excitatory synaptic strength in the nucleus accumbens of rats sensitised to MK-801. An LC-MS/MS proteomics approach demonstrated that proteins altered by MK-801 sensitisationwere predominately related to functions including calcium signalling and mitochondrial dysfunction.I also probed the role of corticosterone signalling using a pharmacological and physiological approach. Pharmacological antagonism of the glucocorticoid receptor with RU486 was found to facilitate behavioural sensitisation to MK-801, potentially through its augmenting effect on MK-801 induced corticosterone levels. Following on from this experiment, I showed that pharmacological antagonism of the stress-related kappa opioid receptor with nor-Binaltorphimine did not have the same effect as RU486. Lastly, I also used LY354740, a pharmacological agonist of the metabotropic glutamate receptors, as a preliminary investigation into the role of glutamatergic transmission. Stimulation of these receptors however was without effect on MK-801 sensitisation.ii Using a range of approaches I have elucidated some of the neural mechanisms and adaptations associated with behavioural sensitisation to MK-801. These results predominately show that sensitisation to MK-801 differs from the mechanism of sensitisation to other drugs of abuse. This model could prove useful for studying the role of NMDARs in the pathophysiology of drug addiction and schizophrenia.iii

show abstract

Mifepristone treatment affects the response to repeated amphetamine injections, but does not attenuate the expression of sensitization

Abstract: Our results indicate that GR-related processes during the initial phase of sensitization are involved in, but not crucial for, the development of long-term sensitization.

Cited by 7 publications

References 33 publications

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

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

Resetting the Stress System with a Mifepristone Challenge

Neural mechanisms of MK-801 induced sensitisation

Contact Info

Product

Resources

About