Differential effects of paroxetine on raphe and cortical 5-HT1A binding: a PET study in monkeys.
Positron emission tomography (PET) ligands that are sensitive to transient changes in serotonin (5-HT) concentration are desirable for studies of neuropsychiatric diseases. Few studies, however, have sought to demonstrate that variations in 5-HT concentration can be closely tracked with available serotonergic ligands. Microdialysis studies in rats have shown a maximal increase in 5-HT concentration in raphe nuclei after systemic infusion of selective serotonergic re-uptake inhibitors (SSRIs). We performed PET scans with [(18)F]FPWAY, an intermediate-affinity antagonist of 5-HT(1A) receptors, in 4 anesthetized rhesus monkeys in control studies and after systemic paroxetine administration (5 mg/kg, i.v.). In addition, a paired [(11)C]DASB study revealed that this paroxetine regimen produced an occupancy of 54-83% of the serotonin transporters. According to the conventional receptor competition model, increased 5-HT concentration produces decreased binding of the radioactive ligand. Over a 3-h period following paroxetine infusion, a progressively increasing reduction (ranging from 8 +/- 6% to 27 +/- 10%) of [(18)F]FPWAY-specific binding was found in the raphe nuclei. This result is interpreted as an SSRI-induced increase in 5-HT concentration, potentially combined with reduced binding to internalized 5-HT(1A) receptors. In addition, a transient (1 h) increase in cerebral cortical binding was observed, attributed primarily to a reduction in cortical 5-HT due to the effects of raphe autoreceptor inhibition. This study is the first demonstration of the feasibility of quantifying dynamic changes in 5-HT neurotransmission in the raphe and the cortex with PET. These results lend promise to the use of these serotonergic neuroimaging techniques to study neuropsychiatric disorders.
PET Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Giampiero
G
Giovacchini
Lixin
L
Lang
Ying
Y
Ma
Peter
P
Herscovitch
William C
WC
Eckelman
Richard E
RE
Carson
D000818:Animals; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D017551:Microdialysis; D017374:Paroxetine / Q000008:administration & dosage / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011903:Raphe Nuclei / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D017374:Paroxetine; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors