MDMA induces EPSP-spike potentiation in rat ventral hippocampus in vitro via serotonin and noradrenaline release and coactivation of 5-HT4 and β1 receptors

Abstract

It is well documented that N-methyl-3,4-methylenedioxyamphetamine (MDMA, ecstasy) releases brain serotonin (5-HT; 5-hydroxytryptamine), noradrenaline (NE; norepinephrine), and dopamine, but the consequent effect on brain functioning remains elusive. In this study, we characterized the effects of MDMA on electrically evoked responses in the ventral CA1 region of a rat hippocampal slice preparation. Superfusion with MDMA (10 μM, 30 min) increased the population spike amplitude (PSA) by 48.9±31.2% and decreased population spike latency (PSL) by 103±139 μs (both: mean±SD, n=123; p<0.0001, Wilcoxon test), without affecting field excitatory postsynaptic potential (fEPSP). This effect persisted for at least 1 h after MDMA washout; we have called this EPSP-spike potentiation (ESP) by MDMA, ESPMDMA. Antagonism of GABAergic transmission did not prevent ESPMDMA, suggesting that an increase in excitability of pyramidal cells underlies this MDMA action. Block of serotonin transporter (SERT) with citalopram or 5-HT depletion with (±)-p-chlorophenylalanine pretreatment partially inhibited the ESPMDMA. Block of both SERT and NE transporter prevented ESPMDMA, indicating its dependence on release of both 5-HT and NE. ESPMDMA is produced by simultaneous activation of 5-HT4 and β1 receptors, with a predominant role of 5-HT4 receptors. Block of both 5-HT4 and β1 receptors revealed an inhibitory component of the MDMA action mediated by 5-HT 1A receptor. The concentration range of MDMA which produced ESP MDMA (1-30 μM) corresponds to that commonly reached in human plasma following the ingestion of psychoactive MDMA doses, suggesting that release of both 5-HT and NE, and consequent ESPMDMA may underlie some of the psychoactive effects of MDMA in humans. © 2008 Nature Publishing Group All rights reserved.