Effect of fenfluramine-induced increases in serotonin release on [18F]MPPF binding: a continuous infusion PET study in conscious monkeys.
[(18)F]MPPF is a selective and reversible antagonist to the serotonin-1A (5-HT(1A)) receptor. The aim of the present study was to investigate whether the binding of [(18)F]MPPF is sensitive to increases in 5-HT levels. We used the 5-HT releasing agent and reuptake inhibitor fenfluramine (FEN) to increase the concentration of 5-HT. [(18)F]MPPF binding was assessed using positron emission tomography (PET) in conscious monkeys. Possible effects of blood flow on ligand binding were excluded by using a bolus-infusion paradigm. Control scans were obtained to assess the state of ligand equilibrium. FEN (5 or 10 mg/kg, i.v.) was administered between 90 and 130 min after the start of the [(18)F]MPPF infusion. The binding potential (BP) was calculated for an early interval (30 min preceding FEN administration) and late interval (20-50 min after administration of FEN). Microdialyses results showed a 20- and 35-fold increase in extracellular 5-HT levels in the prefrontal cortex after injection of FEN at a dose of 5 mg/kg and 10 mg/kg respectively. However, despite these large increases in 5-HT levels, no differences in BP were found between the control and FEN scans. These results may imply that the majority of 5-HT(1A) receptors is in the low affinity state in the living brain.
Udo de Haes
Joanna I
JI
Department of Biological Psychiatry, University Medical Center Groningen, The Netherlands. j.i.udo.de.haes@psy.umcg.nl
Harada
Norihiro
N
Elsinga
Philip H
PH
Maguire
R Paul
RP
Tsukada
Hideo
H
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005277:Fenfluramine / Q000494:pharmacology*; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D017551:Microdialysis / Q000379:methods; D010879:Piperazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D014851:Wakefulness
D005277:Fenfluramine; D010879:Piperazines; D011725:Pyridines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C416325:4-(2'-methoxyphenyl)-1-(2'-(N-2'-pyridinyl)-p-(18F)fluorobenzamido )ethylpiperazine