Metyrapone and Mifepristone Reverse Recognition Memory Loss Induced by Spontaneous Morphine Withdrawal in Mice

Abstract

Morphine withdrawal leads to an increase in corticosterone concentration in plasma, and cognitive deficits are found after withdrawal. Evidence indicates that glucocorticoid hormones affect memory. The aim of the current study was to evaluate the effects of metyrapone and mifepristone on memory deficit following spontaneous morphine withdrawal. Memory was tested by using the object recognition task. The novel object recognition task was carried out in a square wooden open-field apparatus using objects. The test was comprised of three sections: habituation for 15 min., first trial for 12 min. and test trial for 5 min. In this learning paradigm, the difference in exploration between a previously seen object and a novel object is taken as an index of memory performance (recognition index -RI). Male mice were made dependent by increasing doses of morphine (30 -90 mg/kg) subcutaneously twice daily for 3 days. RI was assessed 4 hr after the last dose of morphine on the third day. Mifepristone (50 and 100 mg/kg) and metyrapone (12.5 and 25 mg/kg) were used subcutaneously before the first trial and effects were compared to control values. Metyrapone (25 mg/kg) and mifepristone (50 mg/kg) improved RI to 34.8 ± 10.8% and 25.4 ± 11.7%, respectively, which are significantly different from control values (RI = − 14.8 ± 10.7%, P < 0.05). These results show that increased glucocorticoid concentration may be involved in memory deficit caused by morphine withdrawal. Metyrapone by inhibiting glucocorticoid formation, and mifepristone by inhibiting glucocorticoid receptors may be useful for preventing memory deficit following morphine withdrawal.Brain imaging studies involving human opiate addicts have indicated that many brain areas are hypofunctional during both prolonged abstinence [1] and acute withdrawal [2]. Chronic misuse of opiates will also lead to long-lasting impairments in brain function [3]. This event may relate to the cognitive deficits found, as well as to symptoms of anxiety and depression that linger after the physical symptoms of withdrawal have dissipated [4]. Such effects in human beings will require additional rehabilitation for cognitive deficits that impair everyday function, or else will cause drug-seeking urge. Therefore, looking for pharmacological trends that can prevent this cognitive impairment would be rational.Emotionally arousing experiences activate the hypothalamicpituitary-adrenocortical axis (HPA), resulting in elevated glucocorticoid levels (i.e. corticosterone and cortisol). Morphine withdrawal is associated with activation of the HPA [5]. A study has shown that repeated short periods of drug withdrawal (24 or 72 hr) in morphine-dependent mice represent a mild stress load [6] and animals undergoing acute (12 hr) morphine withdrawal displayed a potentiated and prolonged corticosterone response to restraint [7].Previous studies in both animal and human beings indicate that stress and glucocorticoids modulate various phases of memory processing [8][9][10]. Acute administration of gluco...

Glucocorticoid receptor stimulation and the regulation of neonatal cerebellar neural progenitor cell apoptosis

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The Role of the Glucocorticoids in Developing Resilience to Stress and Addiction

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Mifepristone in the Central Nucleus of the Amygdala Reduces Yohimbine Stress-Induced Reinstatement of Ethanol-Seeking

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