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.
Giovacchini
Giampiero
G
PET Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Lang
Lixin
L
Ma
Ying
Y
Herscovitch
Peter
P
Eckelman
William C
WC
Carson
Richard E
RE
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