The role of corticosteroids in the acquisition of sensitization to locomotor stimulant effects of MK-801.

In the present study, we investigated the role of corticosterone and glucocorticoid receptors in the acquisition of sensitization to locomotor stimulant effects of MK-801 in rats. MK-801 (two doses, 0.4 mg/kg i.p. each, given twice, 48 h apart) evoked sensitization, observed as enhancement of the locomotor activity to a challenging dose of MK-801 (0.4 mg/kg) but not of a stereotypy-like activity. Pharmacological manipulations which deplete endogenous corticosterone, i.e., administration of the corticosterone synthesis inhibitor metyrapone (two injections, 150 and 50 mg/kg, given at 24 and 2 h before the first injection of MK-801, 4 mg/kg) or blockade of glucocorticoid receptors by administration of the antiglucocorticoid RU 38486 (20 mg/kg, 45 min before MK-801, 0.4 mg/kg) abolished the acquisition of sensitization. The obtained results indicate that the endogenous corticosterone and glucocorticoid receptors (type II) are involved in the acquisition of sensitization to locomotor stimulant effects of MK-801. Final experiments showed that MK-801 in doses used in the present study (0.4 mg/kg) enhanced the plasma concentration of corticosterone and that single injection of exogenous corticosterone (10 mg/kg s.c.) enhanced the locomotor stimulant effects of MK-801 (0.2 mg/kg). The obtained data indicate that the acquisition of sensitization to locomotor stimulant effects of MK-801 involves secretion of corticosteroids which probably act through glucocorticoid receptors, as was found previously for amphetamine and its congeners.