A PET study of effects of chronic 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") on serotonin markers in Göttingen minipig brain.
The psychostimulant 3,4-methylendioxymethamphetamine (MDMA, "ecstasy") evokes degeneration of telencephalic serotonin innervations in rodents, nonhuman primates, and human recreational drug users. However, there has been no alternative to nonhuman primates for studies of the cognitive and neurochemical consequences of serotonin depletion in a large-bodied animal. Therefore, we used positron emission tomography (PET) with [(11)C]DASB to map the distribution of plasma membrane serotonin transporters in brain of Göttingen minipigs, first in a baseline condition, and again at 2 weeks after treatment with MDMA (i.m.), administered at a range of doses. In parallel PET studies, [(11)C]WAY-100635 was used to map the distribution of serotonin 5HT(1A) receptors. The acute MDMA treatment in awake pigs evoked 1 degrees C of hyperthermia. MDMA at total doses greater than 20 mg/kg administered over 2-4 days reduced the binding potential (pB) of [(11)C]DASB for serotonin transporters in porcine brain. A mean total dose of 42 mg/kg MDMA in four animals evoked a mean 32% decrease in [(11)C]DASB pB in mesencephalon and diencephalon, and a mean 53% decrease in telencephalic structures. However, this depletion of serotonin innervations was not associated with consistent alterations in the binding of [(11)C]WAY-100635 to serotonin 5HT(1A) receptors. Stereological cell counting of serotonin-positive neurons, which numbered 95,000 in the dorsal raphé nucleus of normal animals, was unaffected in MDMA-treated group. group.
Cumming
Paul
P
PET Centre and Centre for Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark. paul@pet.au.dk
Møller
Mette
M
Benda
Kjeld
K
Minuzzi
Luciano
L
Jakobsen
Steen
S
Jensen
Svend B
SB
Pakkenberg
Bente
B
Stark
Anette K
AK
Gramsbergen
Jan Bert
JB
Andreasen
Mette F
MF
Olsen
Aage K
AK
D000818:Animals; D001596:Benzylamines / Q000493:pharmacokinetics; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging* / Q000187:drug effects*; D001931:Brain Mapping; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D005260:Female; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D010879:Piperazines / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000493:pharmacokinetics; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D013552:Swine; D013556:Swine, Miniature; D014018:Tissue Distribution / Q000187:drug effects
D001596:Benzylamines; D002250:Carbon Radioisotopes; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; D010879:Piperazines; D011725:Pyridines; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D018817:N-Methyl-3,4-methylenedioxyamphetamine