Differential effects of paroxetine on raphe and cortical 5-HT 1A binding: A PET study in monkeys Giampiero Giovacchini, a,b Lixin Lang, a Ying Ma, a Peter Herscovitch, a William C. Eckelman, a and Richard E. Carson a, * a PET Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA b Postgraduate Specialty School in Nuclear Medicine, University of Pisa Medical School, Italy Received 16 February 2005; revised 3 May 2005; accepted 19 May 2005 Available online 1 July 2005 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 T 6% to 27 T 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. Published by Elsevier Inc. Keywords: Paroxetine; 5-HT; Positron emission tomography Introduction The use of positron emission tomography (PET) ligands to detect changes in the concentration of endogenous neurotransmit- ters is valuable to assess the pathophysiology of disease and response to pharmacotherapy (Laruelle, 2000). According to the classical competition model of ligand – receptor kinetics, increased neurotransmitter concentration can produce lower ligand binding levels. On this basis, dynamic changes in dopamine concentration elicited by pharmacological displacement studies have been assessed in control and clinical populations with neuroimaging techniques (Farde et al., 1990; Dewey et al., 1993; Laruelle et al., 1996, 1999; Breier et al., 1997). Unlike the dopamine system, numerous studies have shown no sensitivity of PET serotonergic ligands to agents that alter synaptic serotonin levels (Mathis et al., 1995; Parsey et al., 1997, 1999; Maeda et al., 2001; Rice et al., 2001; Staley et al., 2001; De Haes et al., 2002; Rabiner et al., 2002; Hirani et al., 2003; Pinborg et al., 2004; Talbot et al., 2004). Some other studies, however, have shown the feasibility of measuring changes in serotonergic transmission induced by pharmacological modulations (Hirani et al., 2000; Hume et al., 2001; Ginovart et al., 2003; Milak et al., 2005), although the interpretation of these studies is limited by inconsistent results across cortical regions or complicated by methodological issues affecting tomographic scanning of small laboratory animals (Hume et al., 1998; Gunn et al., 2001). One potential explanation for the absence of robust responses to changes in 5-HT may be the characteristics of the ligand. High affinity ligands have slow cerebral kinetics so that little or no competition for receptor binding might be detected despite rapidly changing 5-HT concentrations. Thus, intermediate-affinity ligands have been hypothesized to be more sensitive to changes in 5-HT concentration with PET (Eckelman, 1998; Endres and Carson, 1998). Studies in animals with positron-sensitive probes yielded results consistent with this hypothesis (Zimmer et al., 2002a, 2003; Rbah et al., 2003). Another possible explanation relates to the difficulties in PET quantification of activity in the raphe. Acute systemic adminis- tration of several serotonergic drugs, including the selective serotonin re-uptake inhibitors (SSRIs) and tricyclics, was shown to elicit the largest increase in 5-HT concentration in the raphe (Adell and Artigas, 1991a; Bel and Artigas, 1992; Invernizzi et al., 1053-8119/$ - see front matter. Published by Elsevier Inc. doi:10.1016/j.neuroimage.2005.05.042 * Corresponding author. Yale University School of Medicine, P.O. Box 208042, New Haven, CT 06520-8042, USA. Fax: +1 203 785 6643. E-mail address: richard.e.carson@yale.edu (R.E. Carson). Available online on ScienceDirect (www.sciencedirect.com). www.elsevier.com/locate/ynimg NeuroImage 28 (2005) 238 – 248