MDMA (3,4-methylenedioxymethamphetamine) inhibits the firing of dorsal raphe neurons in brain slices via release of serotonin

Abstract

The effects of MDMA (3,4-methylenedioxymethamphetamine) on the activity of serotonin (5-HT)-containing dorsal raphe neurons were characterized using extracellular single-unit recording and microdialysis techniques in the in vitro midbrain slice preparation. Addition of (+)-MDMA, (-)-MDMA or p-chloroamphetamine (PCA) to the superfusate (final concentration 3-100 microM) produced a concentration-dependent inhibition of 5-HT cell firing which was reversible and reproducible. Based upon IC50 values, (+)-MDMA was 2- to 3-fold more potent than (-)-MDMA. Pretreatment with the selective 5-HT uptake inhibitor fluoxetine, at a concentration which had no effect on baseline firing (20 microM), blocked the inhibitory effect of (+)-MDMA and PCA on dorsal raphe neurons. The selective norepinephrine uptake inhibitor desipramine (20 microM) was ineffective. In a parallel series of experiments, microdialysis probes resting on the brain slice surface provided a means to estimate 5-HT release from the dorsal raphe nucleus. (+)-MDMA (100 microM) caused the release of measureable quantities of 5-HT with a time course which corresponded to the change in dorsal raphe cell firing rate. Taken together, these data suggest that MDMA acts indirectly to inhibit dorsal raphe neurons through release of endogenous 5-HT.