The effect of dexamethasone (DEX) and its interaction with psychostimulants agents (morphine, cocaine and amphetamine) has been studied on locomotor activity and straub reaction in mice: a) Morphine administration, (30-75-150 mg/kg,ip) induced a dose-related increase of the locomotor activity of mice, whereas DEX per se (0.1-1.0-10 mg/kg,ip) did not modify the activity of control mice. Pretreatment of mice with DEX 0.1 mg did not alter the hyperactivity produced by the three doses of morphine. In contrast, DEX administered at 1.0 mg reduced the morphine effects on locomotor activity, whereas DEX at 10 mg potentiated the morphine hypermotility. b) Cocaine (10 mg/kg/i.p.) and amphetamine (5 mg/kg/i.p.) increased markedly locomotor activity of mice whereas DEX per se (0.1-1.0- 10 mg/kg/i.p.) did not modify the activity of control mice. DEX pretreatment decreased the stimulating effects induced by cocaine and amphetamine. DEX pretreatment 0, 15, 30, 60 and 120 min before amphetamine or cocaine strongly decreased both amphetamine and cocaine effects, but no dose-related effect was observed. The time-course study performed with DEX revealed differences in its reducing effect on cocaine and amphetamine hypermotility when the groups of animals treated with the steroid immediately before the cocaine (or amphetamine) injection when compared to those treated with the steroid later (15, 30, 60 and 120 min). Furthermore, actinomycin D was able to block the reducing effect of DEX on both amphetamine and cocaine hypermotility. c) When morphine was administered in doses of 7.5, 15 and 30 mg/kg/i.p, a dose-dependent straub reaction was produced. DEX per se (0.1-1.0-10 mg /kg,i.p.) did not modify the tail of control mice. Pre-treatment with DEX 120 min before morphine injection caused a dose-dependent reduction of straub reaction. Cycloheximide (15 mg/kg,i.p.) administered 2h before morphine did not change morphineinduced straub reaction, but was able to prevent the effects of DEX on morphine-induced straub reaction. The glucocorticoid receptor antagonist RU-38486 (15 mg/kg,i.p.) did not affect morphine-induced straub reaction, whereas it was able to block the effects of dexamethasone on morphine-induced straub reaction. Our results suggest that DEX may play an important regulatory role on the central effects of morphine, cocaine and amphetamine through a differential modulation of brain excitability systems indicating that DEX may play an important role on the stimulating effects of morphine, cocaine and amphetamine and that it may be of some utility in the clinical management of psychastimuants abuse. The ability of actinomicyn D and/or cycloheximide as well as of RU-38486 to block dexamethasones effects indicates that the steroids interference with psychostimulants-mediated effects involve a protein-synthesis-dependent mechanism via glucocorticoid receptors. The patents related to psychostimulant agent and glucocorticoids are also discussed in this article.