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MDMA‐evoked changes in the binding of dopamine D 2 receptor ligands in striatum of rats with unilateral serotonin depletion
Author(s) -
Østergaard Søren Dinesen,
Alstrup Aage Kristian Olsen,
Gramsbergen Jan Bert,
Minuzzi Luciano,
Pedersen Kasper,
Jensen Svend Borup,
Doudet Doris,
Cumming Paul
Publication year - 2010
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20706
Subject(s) - raclopride , dopamine , mdma , chemistry , serotonin , striatum , 5 ht receptor , medicine , endocrinology , pharmacology , receptor , biology , biochemistry
We earlier reported an anomalous 50% decrease in [ 11 C] N ‐methylspiperone ([ 11 C]NMSP) binding to dopamine D 2 ‐like receptors in living pig striatum after challenge with 3,4‐methylenedioxymethamphetamine (MDMA, “Ecstasy”), suggesting either (1) a species peculiarity in the vulnerability of butyrophenone binding to competition from dopamine or (2) a novel consequence of synergistic actions of serotonin and dopamine at dopamine receptors. To distinguish these possibilities, we used microPET to test the vulnerability of [ 11 C]NMSP binding in striatum of rats with unilateral telencephalic serotonin lesions, later verified by [ 125 I]RTI‐55 autoradiography. Baseline [ 11 C]NMSP microPET recordings were followed by either saline or MDMA‐HCl (4 mg/kg) injections (i.v.), and a second [ 11 C]NMSP recording, culminating with injection of [ 3 H]raclopride for autoradiography ex vivo. Neither MDMA‐challenge nor serotonin lesion had any detectable effect on [ 11 C]NMSP binding. In contrast, MDMA challenge increased receptor occupancy by [ 3 H]raclopride ex vivo (relative to the B max in vitro) from 8% to 12%, and doubled the free ligand concentration in cerebral cortex, apparently by blocking hepatic CYP2D6. Assuming a single binding‐site model, the increased [ 3 H]raclopride binding indicated doubling of the apparent equilibrium dissociation constant in vivo ( K app d ), revealing a 2‐fold increase in competition from endogenous dopamine at [ 3 H]raclopride binding sites. The results favor hypothesis (1) that the remarkable vulnerability of [ 11 C]NMSP binding in pig striatum to MDMA challenge does not generalize to the rodent. Synapse 64:70–82, 2010. © 2009 Wiley‐Liss, Inc.