We previously reported that
6-methoxy-1,2,3,4-tetrahydro-beta-carboline (6-MeO-THBC) attenuated audiogenic
seizures (AGS) in 21-day-old DBA/2J mice and also inhibited brain
monoamine oxidase-A (
MAO-A) and
serotonin (5-hydroxytryptamine, 5-HT) uptake leading to increased brain
5-HT concentration. In this study, the sensitivity of AGS to
5-HT manipulation was evaluated by utilizing
drug combinations which paralleled the actions of 6-MeO-THBC and which also have been associated with the production of a serotonergic motor syndrome in rats. Combination of a specific
5-HT uptake inhibitor (
fluoxetine or
citalopram) with the
MAO-A inhibitor
clorgyline inhibited AGS more effectively than the individual drugs but combination with the
MAO-B inhibitor
deprenyl did not. Combined administration of
clorgyline plus
deprenyl also suppressed AGS. Inhibition of AGS by
tryptophan was potentiated by combination with either of the mixed
MAO inhibitors nialamide or
tranylcypromine. The effects of these drugs individually and in combination on brain
MAO-A and
MAO-B activity and
5-HT uptake were also determined ex vivo and were consistent with expected mechanisms of action. These results suggest, first of all, that the inhibition of AGS produced by 6-MeO-THBC is a consequence of its combined
MAO-A and
5-HT uptake inhibition properties. Secondly, the similarity of results of pharmacological manipulations of the
5-HT system which produce the rat motor syndrome and which inhibit AGS in the mouse suggests that AGS in 21-day-old DBA/2J mice may be a useful system for assessing functional consequences of these serotonergic manipulations.