Low striatal serotonin transporter protein in a human polydrug MDMA (ecstasy) user: a case study

A post-mortem analysis of a high-dose MDMA user's brain found that protein levels of the serotonin transporter (SERT) were markedly reduced in the striatum and occipital cortex (by 48–58%) and less affected in frontal and temporal cortices (by 25%), while tryptophan hydroxylase (TPH), the enzyme that synthesizes serotonin, was severely decreased in the caudate and putamen (by 68% and 95%, respectively). The reduction in striatal SERT protein was larger than the binding decreases typically reported in imaging studies. These results suggest high-dose MDMA exposure may cause loss of two key protein markers of serotonin neurons, possibly indicating physical damage or downregulation of neuronal components.

Study at a glance

Abstract

Evidence that the widely used methamphetamine analog MDMA (3,4-methylenedioxymethamphetamine, ecstasy) might damage brain serotonin neurones in humans is derived from imaging investigations showing variably decreased binding of radioligands to the serotonin transporter (SERT), a marker of serotonin neurones. However, in humans, it is not known whether low SERT binding reflects actual loss of SERT protein itself. As this question can only be answered in post-mortem brain, we measured protein levels of SERT and that of the rate-limiting serotonin-synthesizing enzyme tryptophan hydroxylase (TPH) in autopsied brain of a high-dose MDMA user. As compared with control values, SERT protein levels were markedly (−48% to −58%) reduced in striatum (caudate, putamen) and occipital cortex and less affected (−25%) in frontal and temporal cortices, whereas TPH protein was severely decreased in caudate and putamen (−68% and −95%, respectively). The magnitude of the striatal SERT protein reduction was greater than the SERT binding decrease typically reported in imaging studies. Although acknowledging limitations of a case study, these findings extend imaging data based on SERT binding and suggest that high-dose MDMA exposure could cause loss of two key protein markers of brain serotonin neurones, a finding compatible with either physical damage to serotonin neurones or downregulation of components therein.