Characterization of acute N-ethyl-3,4-methylenedioxyamphetamine (MDE) action on the central serotonergic system.

The effect of N-ethyl-3,4-methylenedioxyamphetamine (MDE) on the central serotonergic system was studied. Within 1 hr after administration of MDE (10 mg/kg), the concentration of 5-hydroxytryptamine (5-HT) and the activity of tryptophan hydroxylase (TPH) had declined significantly in the hippocampus but returned to control within 12 hr. Hippocampal 5-hydroxyindoleacetic acid (5-HIAA) content decreased within 2 hr, rebounded to 22% above control by 12 hr, and returned to control by 24 hr. Blockade of the 5-HT uptake carrier with fluoxetine (10 mg/kg) prevented or attenuated the MDE-induced changes in 5-HT content and TPH activity, except for neostriatal TPH activity which remained unresponsive to the fluoxetine treatment. The MDE-induced decline in TPH activity could be reversed by incubating the TPH preparation with dithiothreitol and Fe2+ under nitrogen for 24 hr. This suggests that the loss in TPH activity induced by MDE results from an alteration of the oxidation-reduction state of a sulfhydryl group located on the enzyme. The inhibition of monoamine oxidase (MAO) by the administration of pargyline (75 mg/kg) failed to protect the neostriatal TPH activity from the MDE-induced decline while potentiating the MDE-induced decrease in cortical TPH activity. This suggests that H2O2 generated by MAO in vivo is not responsible for oxidation of the sulfhydryl site located on TPH during the MDE treatment.