Repeated amphetamine administration down-regulates glucocorticoid, but not mineralocorticoid, receptors in the rat hippocampus.

It has been postulated that activation of the hypothalamic-pituitary-adrenal (HPA) axis is critical to the development of sensitization to amphetamine. Since this axis is under inhibitory control of hippocampal corticosteroid receptors, the present study has been designed to determine the effects of repeated (5 mg/kg, ip, twice a day for 14 days) d-amphetamine (AMPH) administration on binding parameters of these receptors. Glucocorticoid (GR) and mineralocorticoid (MR) receptors were examined by an in vitro [3H]corticosterone binding in the cytosol from the rat hippocampus, using the selective GR agonist RU 28362 to discriminate between MR and GR. Repeated, but not single, treatment with AMPH significantly reduced the density of GR (decrease by ca. 20%). The density of MR tended to decrease 2 h, but not 72 h, after the last drug injection. No changes in dissociation constants were found following single or repeated AMPH administration. The plasma corticosterone level was significantly increased 1, 2 and 72 h after chronic administration of AMPH. Obtained results indicate that repeated AMPH administration down-regulates GR receptors and increases plasma corticosterone level. These changes may reflect neurochemical mechanism of addictive properties of AMPH.