Positron emission tomographic studies of brain dopamine and serotonin transporters in abstinent (+/-)3,4-methylenedioxymethamphetamine ("ecstasy") users: relationship to cognitive performance.
BACKGROUND
(+/-)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.


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.


RESULTS
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.


CONCLUSIONS
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.
McCann
Una D
UD
Department of Psychiatry, The Johns Hopkins School of Medicine, Baltimore, MD 21224, USA. umccann@jhmi.edu
Szabo
Zsolt
Z
Vranesic
Melin
M
Palermo
Michael
M
Mathews
William B
WB
Ravert
Hayden T
HT
Dannals
Robert F
RF
Ricaurte
George A
GA
D000293:Adolescent; D000328:Adult; D019969:Amphetamine-Related Disorders / Q000000981:diagnostic imaging* / Q000534:rehabilitation; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D011939:Mental Recall / Q000187:drug effects; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D018490:Serotonin Agents / Q000633:toxicity; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D055815:Young Adult
D050483:Dopamine Plasma Membrane Transport Proteins; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D018817:N-Methyl-3,4-methylenedioxyamphetamine