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

Abstract

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 Fe 2+ 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 H 2O 2 generated by MAO in vivo is not responsible for oxidation of the sulfhydryl site located on TPH during the MDE treatment.