Sustained recreational use of ecstasy is associated with altered pre and postsynaptic markers of serotonin transmission in neocortical areas: a PET study with [¹¹C]DASB and [¹¹C]MDL 100907

Abstract

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT(2A) receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT(2A) receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT(2A) receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT(2A) receptor availability (binding potential, BP(ND)) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP(ND) and higher 5-HT(2A) receptor BP(ND) in cortical, but not subcortical regions. Decreased SERT BP(ND) was regionally associated with upregulated 5-HT(2A) receptor BP(ND). In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.

Figure 1

Parametric map of BP_ND of the serotonin transporter ligand [¹¹C]DASB (top) and the 5-HT_2A receptor [¹¹C]MDL 100907 (bottom) computed for 13 MDMA users (XTC, right column) and 13 healthy control subjects (HC, middle column). Individual BP_ND maps were generated for each subject and were nonlinearly transformed into a common template space. The co-registered structural MRIs with lines indicating the planes of view (coronal and transverse) on the left are the average from four subjects. Displayed are the regions of highest ligand binding. Regions of high [¹¹C]DASB binding are subcortical (striatum, thalamus, midbrain), while to signal is very faint in cortical regions. The reverse is true for [¹¹C]MDL 100907. [¹¹C]MDL 100907 binding is higher in cortical regions, and [¹¹C]MDL 100907 specific binding is barely detectable in subcortical regions.

Figure 2

Scattergrams of [¹¹C]DASB (two top rows) and [¹¹C]MDL 100907 (lower row) BP_ND values in MDMA users and control subjects in selected cortical regions: medial temporal lobe (MTL), medial frontal cortex (MFC), temporal cortex (TEMP), occipital cortex (OCC), dorsolateral prefrontal cortex (DLPFC), and parietal cortex (PAR).

Figure 3

Voxel-wise group mean comparisons of [¹¹C] MDL 100907 and [¹¹C]DASB BP_ND between MDMA (XTC) and HC subjects. Each subject's PET data were analyzed using a 1TC model for both ligands. Individual BP_ND maps were normalized to a T1-weighted, single subject MRI template. Data were smoothed with a 12-mm FWHM Gaussian kernel. Group means were compared using a two-group t statistic. There were widespread clusters of voxels in cortical regions reaching trend level difference for XTC < HC with [¹¹C]DASB BP_ND (top: occipital, parietal, and prefrontal cortices, p=0.08, FDR corrected) and for XTC > HC with [¹¹C] MDL 100907 BP_ND (bottom: parietal and dorsolateral prefrontal cortex, p=0.06, FDR corrected) that, in general coincided with the ROI analysis results. The display threshold was set at p⩽ 0.01. The vertical line in each view shows the slice level of the other view for that ligand. The color scale represents the values of the t statistic.

Figure 4

Association between the percent difference in group means for the two ligands in the seven cortical regions (DLPFC, dorsolateral prefrontal cortex; MPFC, medial prefrontal cortex; OFC, orbiotfrontal cortex; occipital cortex, parietal cortex, temporal Ctx, MTL, medial temporal lobe). For each ligand and each region, data are expressed as percent change compared with controls. R is the Pearson product moment correlation coefficient; the p-value is for a two-tailed t-test with 5 df. Cortical regions with the lowest [¹¹C]DASB BP (x axis) showed the highest in [¹¹C]MDL 100907 BP. This was significant at trend level. Interestingly, the two medial regions (MPFC and MLT) showed the smallest change, presumably due to relatively shorter axonal length.