MDMA (‘ecstasy’) enhances basal acetylcholine release in brain slices of the rat striatum

MDMA (ecstasy) increases the release of the neurotransmitter acetylcholine in rat striatal brain slices in a dose-dependent manner, with a half-maximal effect at about 30 µM. This effect requires calcium and is blocked by tetrodotoxin, indicating it depends on neuronal firing. Blocking glutamate, dopamine D2, serotonin 5-HT1, 5-HT2, 5-HT3C, or muscarinic acetylcholine receptors did not alter MDMA's effect, but blocking histamine H1 receptors completely abolished the acetylcholine release. The findings suggest MDMA directly activates histamine H1 receptors to stimulate striatal cholinergic neurons, revealing a previously unknown neurochemical pathway for MDMA's acute effects.

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Abstract

Abstract The pharmacological basis of acute (±)‐MDMA (3,4‐methylenedioxymethamphetamine) intoxication still awaits full characterization. According to present knowledge, MDMA enhances the release of serotonin and dopamine in striatal slices and interacts with different types of receptors such as 5‐HT 2 (5‐hydroxytryptamine or serotonin), M 1 and M 2 muscarinic acetylcholine (ACh), and histamine H 1 receptors. Currently, no information is available about the influence of (±)‐MDMA on striatal cholinergic neurotransmission. In the present study, we used the in vitro perfusion technique to investigate the effect of (±)‐MDMA on ACh release in rat striatal slices. Perfusions with (±)‐MDMA (10–300 μ m ) resulted in a dose‐dependent increase of spontaneous ACh release (EC 50 ≈ 30 μ m ). The effect was reversible and Ca ++ ‐ and tetrodotoxin‐sensitive. To determine the neurochemical pathways underlying this response, we perfused with (±)‐MDMA in the presence of various inhibitors of neurotransmitter receptors. Blockade of glutamate or muscarinic ACh receptors as well as 5‐HT 1 , 5‐HT 2 , 5‐HT 3C or dopamine D 2 receptors did not modulate (±)‐MDMA–induced ACh release. However, the presence of histamine H 1 receptor antagonists in the perfusion medium abolished (±)‐MDMA‐induced ACh release. The present data clearly demonstrate that (±)‐MDMA enhances the activity of striatal cholinergic neurons and suggest an involvement of histamine H 1 receptors. The effect is not mediated by glutamate and does not involve the activation of receptors of dopamine D 2 , 5‐HT 1 , 5‐HT 2 , 5‐HT 3C or muscarinic ACh. Considering the relatively high affinity of (±)‐MDMA for the H 1 histamine receptor (Ki 6 μ m ), a direct activation of this type of receptor might represent a plausible mechanism for (±)‐MDMA‐induced ACh release.