MDMA-evoked changes in the binding of dopamine D(2) receptor ligands in striatum of rats with unilateral serotonin depletion.
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.
Ostergaard
Søren Dinesen
SD
Aarhus University Positron Emission Tomography (PET) Center, Aarhus University Hospital, DK-8000 Aarhus C, Denmark. soerendinesen@gmail.com
Alstrup
Aage Kristian Olsen
AK
Gramsbergen
Jan Bert
JB
Minuzzi
Luciano
L
Pedersen
Kasper
K
Jensen
Svend Borup
SB
Doudet
Doris
D
Cumming
Paul
P
D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D002250:Carbon Radioisotopes / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D006213:Hallucinogens / Q000493:pharmacokinetics*; D007091:Image Processing, Computer-Assisted; D008024:Ligands; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D020891:Raclopride / Q000493:pharmacokinetics; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012701:Serotonin / Q000172:deficiency; D013134:Spiperone / Q000378:metabolism*
D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D006213:Hallucinogens; D008024:Ligands; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D012701:Serotonin; D020891:Raclopride; D013134:Spiperone; D018817:N-Methyl-3,4-methylenedioxyamphetamine