Repeated cocaine administration down-regulates glucocorticoid receptors in the rat brain cortex and hippocampus

Chronic exposure to psychostimulants results in an aberrant activity of the hypothalamic-pituitary-adrenal (HPA) axis. Since this axis is under inhibitory control of corticosteroid receptors, the present study has been designed to determine the effects of repeated (15 mg/kg, ip, once an hour for 3 h, for 8 days) cocaine administration on cytosolic and nuclear glucocorticosteroid receptor (GR) levels in the hippocampus and frontal cortex of the rat. As shown by a sensitive Western blotting technique, repeated (but not single) treatment with cocaine significantly reduced the density of cytosolic GR in the frontal cortex (by ca. 23%) and to a lesser extent in the hippocampus (by ca. 10%), after 45 min and 72 h, respectively. No changes in the nuclear fraction of the GR level were found following repeated cocaine administration, whereas acute treatment enhanced the signal in the hippocampus by ca. 17%. The obtained results indicate that repeated cocaine administration decreases the level of GR in the cytosol, but does not enhance transport of these receptors into the nuclei. The down-regulation of cortical and hippocampal GR receptors may play some role in the cocaine-induced impairment of the feedback control mechanism of the HPA axis activity.