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 mM, 30 min) increased the population spike amplitude (PSA) by 48.9731.2% and decreased population spike latency (PSL) by 1037139 ms (both: mean7SD, n ¼ 123; po0.0001, 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, ESP MDMA . Antagonism of GABAergic transmission did not prevent ESP MDMA , 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 (7)

Differential modulation of CA1 impulse flow by endogenous serotonin along the hippocampal longitudinal axis

“…Part of data (∼30% of the values for MDMA effect in the ventral hippocampus) derive from reanalysis of previously published experiments in which the experimental protocol and coding of slices were consistent with the criteria of the present study (Mlinar et al, ). For statistical comparison, the steady‐state values were computed by averaging 11 or 21 consecutive responses obtained over 5 min period immediately before MDMA application (baseline value) and at 25–30 min of drug superfusion.…”

“…In the CA1 region, MDMA affects neurotransmission by releasing both 5‐HT and NA. The contribution of each monoamine can be discriminated by using selective inhibitors of the respective high‐affinity plasma membrane transporters (Mlinar et al, ). As shown in Figure a,b, in the presence of the selective NA transporter inhibitor, nisoxetine (200 nM), that prevents MDMA‐induced NA release, the MDMA effect was strongly correlated with the dorsoventral position ( r = 0.608, p < .0001; n = 37), indicating that the gradient was generated by the release of endogenous 5‐HT and not by NA.…”

“…Recording procedures and equipment have been detailed previously (Mlinar et al, ). After disconnecting the CA1 and CA3 areas by a surgical cut, the slice was submerged in the recording chamber and superfused with warmed (31–32 °C), oxygenated artificial cerebrospinal fluid at a flow rate of ∼2 mL min −1 .…”

“…The rationale for the choice and the concentrations of drug used has been detailed previously (Mlinar et al, ). MDMA (1–10 µM) was used to elicit the release of endogenous 5‐HT and NA.…”

“…Previous studies from our laboratory (e.g., Mlinar & Corradetti, ; Mlinar et al, ) and others (Segal, ; Winterer et al, ) have shown that serotonergic releasers such as MDMA, p‐methylthioamphetamine and fenfluramine produce multiple effects on the electrical properties of pyramidal neurons and the impulse flow in hippocampal CA1. In the only study in which the precise position of the slices along the dorsoventral axis was reported (20–40% of longitudinal axis from the ventral pole, Mlinar et al, ), MDMA‐induced release of 5‐HT and NA produced an increase in the PSA in CA1 via activation of 5‐HT 4 and β 1 receptors, respectively. In the present study, we sought to extend those results by examining how the effects of MDMA‐induced release of 5‐HT and NA depend on the position of the slices along the entire extent of the dorsoventral hippocampal axis.…”