The effect of dexamethasone (DEX) on brain excitability has been studied by using locomotor activity, straub reaction and epilepsy tests:
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 were 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 morphine-induced 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.
d. The inhibitory effects exerted by DEX on the epileptiform activity induced by morphine were investigated in two different experimental modeis with two different animal species. In the first series of experiments, DEX administered i.v. in rabbits 30 min before i.c.v. administration of morphine completely prevented both epileptiform and background EEG as well as behavioral alterations induced by morphine. Cycloheximide (a protein synthesis inhibitor) pretreatment reversed the antagonistic effect induced by DEX on the behavioral and EEG alterations induced by morphine. In the second series of experiments, the effects exerted by DEX were investigated on morphineinduced CA1 epileptiform bursting on rat hippocampal slices in vitro. DEX pretreatment 10 to 60 min before morphine strongly prevented the morphine effects in a concentration- and time-dependent manner. Sixty min of DEX pretreatment also prevented the epileptiform bursting induced by the selective µ optate receptor agonist DAMGO, whereas it did not significantly affect the increase of the CA1 population spike amplitude due to the selective d opiate receptor agonist DPDPE. The addition of cycloheximide to the slice-perfusing medium containing DEX prevented the inhibitory effects of the drug toward the morphine and DAMGO-induced CA1 epileptiform bursting. Our results indicate that DEX induces an inhibition on the epileptiform activity induced by morphine and DAMGO. The time lag (30-60 min) which is necessary for revealing the inhibitory influence of DEX on opiate epileptiform activity induced both in vivo and in vitro, and the inhibitory effect exerted by cycloheximide on DEX activity strongly support the hypothesis of a genomic corticosteroid effect within the central nervous system.
e. The effects of DEX and RU-38486 plus DEX on the neocortical spikeand- wave spindling episodes (S) in the ECoG of DBA/2J mice was also investigated.
DEX (1-10-100 μg/kg/i.p.) dose-dependently reduce the S of DBA/2J mice. This effect appears 30 min after drugs administration and lasts for the duration of the recording period (240 min). RU-38486, a glucocorticoid receptor antagonist, (1-10-100 μg/kg/i.p.) injected two hours before DEX, was able to block totally the steroid effect.
These results further indicate that DEX induces significant reduction on S of DBA/2J mice confirming the ability of DEX to control brain excitability.
Our results suggest that DEX plays an important regulatory role on the brain excitability. The ability of actinomicyn D and/or cycloheximide as well as of RU- 38486 to block DEX's effects indicates that the steroid acts through the involvement of a protein-synthesis-dependent mechanism via glucocorticoid receptors.
