The effects of spironolactone on morphine withdrawal induced memory loss by the object recognition task method in mice

Abstract

Previous reports showed that elevated levels of glucocorticoids following morphine withdrawal play an important role in memory impairment. In addition, glucocorticoid receptor (GR) inhibitors improved memory perfor-mance in morphine withdrawal mice. Since mineralocorticoid receptor (MR) and GRs complement each other, the aim of the current study was to evaluate the effects of spironolactone on memory performance after withdrawal in morphine dependent mice. To assess memory performance, the object recognition task was used. 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 three days. Withdrawal was elicited either by injection of naloxone (0.1 mg/kg) 3 h after last morphine injection or spontaneously 4 h after the last dose of morphine on the third day. Spironolactone (50, 100 mg/kg) was used subcutaneously before the first trial and the effects were compared with control values. After naloxone precipitated withdrawal spironolactone at 50 and 100 mg/kg improved RI to 10.8% ± 6.0 and 24.0% ± 6.1 which were significantly different from vehicle (RI=-24.1 % ± 6.6, P<0.05). Following spontaneous withdrawal, spironolactone at 50 mg/kg improved RI to 18.0% ± 13.0 that differed significantly from vehicle (RI=-20.8% ± 11.4, P<0.01). Results of these experiments show that MRs may play an important role in the recognition memory impairment following morphine withdrawal in mice.