Low striatal serotonin transporter protein in a human polydrug MDMA (ecstasy) user: a case study.
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.
Kish
S J
SJ
Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada. stephen_kish@camh.net
Fitzmaurice
P S
PS
Chang
L J
LJ
Furukawa
Y
Y
Tong
J
J
D000328:Adult; D001344:Autopsy; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D018490:Serotonin Agents / Q000633:toxicity; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000187:drug effects / Q000378:metabolism
D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D014365:Tryptophan Hydroxylase; D018817:N-Methyl-3,4-methylenedioxyamphetamine