Positron emission tomographic studies of brain dopamine and serotonin transporters in abstinent (±)3,4-methylenedioxymethamphetamine (“ecstasy”) users: relationship to cognitive performance
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(±)3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a recreational drug and brain serotonin (5-HT) neurotoxin. Under certain conditions, MDMA can also damage brain dopamine (DA) neurons, at least in rodents. Human MDMA users have been found to have reduced brain 5-HT transporter (SERT) density and cognitive deficits, although it is not known whether these are related. This study sought to determine whether MDMA users who take closely spaced sequential doses, which engender high plasma MDMA concentrations, develop DA transporter (DAT) deficits, in addition to SERT deficits, and whether there is a relationship between transporter binding and cognitive performance.
Materials and methods
Sixteen abstinent MDMA users with a history of using sequential MDMA doses (two or more doses over a 3- to 12-h period) and 16 age-, gender-, and education-matched controls participated. Subjects underwent positron emission tomography with the DAT and SERT radioligands, [11C]WIN 35,428 and [11C]DASB, respectively. Subjects also underwent formal neuropsychiatric testing.
MDMA users had reductions in SERT binding in multiple brain regions but no reductions in striatal DAT binding. Memory performance in the aggregate subject population was correlated with SERT binding in the dorsolateral prefrontal cortex, orbitofrontal cortex, and parietal cortex, brain regions implicated in memory function. Prior exposure to MDMA significantly diminished the strength of this relationship.
Use of sequential MDMA doses is associated with lasting decreases in brain SERT, but not DAT. Memory performance is associated with SERT binding in brain regions involved in memory function. Prior MDMA exposure appears to disrupt this relationship. These data are the first to directly relate memory performance to brain SERT density.
KeywordsPositron emission tomography Amphetamines Pharmacokinetics Neurotoxicity Serotonin Dopamine Memory
We thank Kristen Kelley and Emily Dotter for their help in the data analyses and figure preparation and appreciate the following contributions to PET imaging and image analysis: Jozsef Varga, Ph.D., for the software design and implementation of the PMT software package that was used for image registration and ROI analysis; Tomas Zober, MD, for determinations of the input functions, computer network, and database management; David Clough, CNMT, and Karen Edmonds, CNMT, for the performance of PET studies; and John Hilton for the HPLC analysis of tracer metabolites. This manuscript was supported by PHS Grants DA10217 (McCann); DA05938; DA13790, DA09487, DA017964 (Ricaurte); AA11653 (Szabo) and NCRR grant M01RR002719 (Ford).
None of the authors has a biomedical financial conflict of interest or other conflict of interest that might potentially bias this work.
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