Paradoxical effects of low dose MDMA on latent inhibition in the rat

Abstract

The cognitive effects of MDMA (‘Ecstasy’) are controversial, particularly in the case of acute administration of low doses. Latent inhibition (LI) refers to the reduction in conditioning to a stimulus that has received non-reinforced pre-exposure, an effect typically abolished by amphetamines and enhanced by antipsychotics. LI enhancement has also been shown using the 5-HT reuptake blocker sertraline. In the present study, the effects of MDMA (6 mg/kg, known to increase 5-HT release) were tested using 10 and 40 pre-exposures to produce weak and strong LI in controls, respectively. MDMA (injected twice, prior to pre-exposure and conditioning) significantly enhanced LI in that the effect was clearly demonstrated after only 10 pre-exposures, when it was absent in the saline controls. On its own such a profile of action would be consistent with a procognitive effect of MDMA mediated by increased availability of 5-HT. However, paradoxically the same MDMA treatment reduced LI in the 40 pre-exposures condition. This component of action is likely attributable to MDMA's actions on catecholaminergic systems and is consistent with other evidence of its adverse effects. Moreover, there were small but significant reductions in 5-HT in medial prefrontal cortex (mPFC) and amygdala assayed 7 days post MDMA administration (2 × 6 mg/kg, 24 h apart).

Data showing regional differences in rat brain monoaminergic function

“…These are of interest in their own right and can in principle be taken into account in statistical models of functional interconnectivity mediated by the monoamines. When samples are taken to verify the effectiveness of an experimental intervention such as the injection of a neurotoxin, the convention is to pool the samples from the right and left hemispheres prior to analysis and this is the approach that we have previously adopted, to assess the effects of dopaminergic depletion using 6-OHDA [[3], [4], [5]], serotonergic depletion using 5,7-DHT [6], and systemic MDMA [7].…”

“…These are fully described in the earlier published papers [[3], [4], [5], [6], [7]]. All procedures conducted prior to the post mortem tissue sampling and assays were carried out in accordance with the United Kingdom (UK) Animals Scientific Procedures Act 1986, Project Licence number: PPL 40/3163.…”

“…Thus the effect of laterality can be investigated for these regions ( N = 100 for NAc and DLS, N = 53 for Amyg). However, there was no differentiation of NAc sub-regions in the study of the effects of systemic MDMA in which a larger punch was used [7]. Caudate putamen [3,5,6] and DLS [4] refer to the same sample (the same punch was used to extract the anatomically equivalent sample) and these samples are all labelled DLS in the dataset.…”

MDMA modulates spontaneous firing of subthalamic nucleus neurons in vitro

“…Alongside a controversial discussion of the beneficial versus harmful potential of MDMA (Green et al 2012;Parrott 2012), the effects of the drug continue to be investigated, e.g. on cognition (Mithoefer et al 2013;Nelson et al 2013) and the motor system (Baumann et al 2008). Specifically, an antidyskinetic effect of MDMA, reported anecdotally about a decade ago (Margolis 2001), was confirmed in in vivo research and could be attributed to MDMA's interaction with the serotonergic (5-hydroxytryptamine, 5-HT) transmitter system Banjaw et al 2003;Iravani et al 2003;Bishop et al 2006;Huot et al 2011;Lettfuss et al 2012).…”

Chronic exposure to MDMA ( Ecstasy ) Induces DNA Damage , Impairs Functional Antioxidant Cellular Defenses , Enhances the Lipid Peroxidation Process and Alters Testes Histopathology in Male Rat

“…MDMA is almost taken by mouth and is prepared as single-dose tablets for this purpose, though the great majority consist of a single active drug. The typical dosage range of MDMA for recreational use varies from 50 mg to 150 mg, but the amount per tablet in different batches of tablets may vary 70-fold or more, from almost zero to well over 100 mg ( 5,6,7). MDMA and the other ringsubstituted amphetamine derivatives act by increasing the net release of the monoamine neurotransmitters (serotonin, noradrenaline and, to a smaller extent, dopamine) from their respective axon terminals.…”