5-HTTLPR status predictive of neocortical 5-HT 4 binding assessed with [ 11 C] SB207145 PET in humans Patrick M. Fisher a, b , Klaus K. Holst a, b , Brenda Mc Mahon a, b , Mette E. Haahr a, b , Karine Madsen a, b , Nic Gillings a, c , William F. Baaré a, d , Peter S. Jensen a, b , Gitte M. Knudsen a, b, ⁎ a Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen O, Denmark b Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen O, Denmark c PET and Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen O, Denmark d Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark abstract article info Article history: Accepted 4 May 2012 Available online 11 May 2012 Keywords: Imaging genetics Serotonin 5-HTTLPR 5-HT 4 receptor [ 11 C]SB207145 Positron emission tomography Serotonin (5-HT) is a neuromodulator affecting myriad aspects of personality and behavior and has been im- plicated in the pathophysiology of affective disorders including depression and anxiety. The 5-HTTLPR is a common genetic polymorphism within the promoter region of the gene coding for the serotonin transporter such that the S allele is associated with reduced transcriptional efficacy compared to the L allele, potentially contributing to increased serotonin levels. In humans, this genetic variant has been linked to inter-individual variability in risk for affective disorders, related aspects of personality and brain function including response to threat. However, its effects on aspects of serotonin signaling in humans are not fully understood. Studies in animals suggest that the 5-HT 4 receptor (5-HT 4 ) shows a monotonic inverse association with long-term changes in serotonin levels indicating that it may be a useful measure for identifying differences in serotonergic neurotransmission. In 47 healthy adults we evaluated the association between 5-HTTLPR sta- tus and in vivo 5-HT 4 receptor binding assessed with [ 11 C]SB207145 positron emission tomography (PET). We observed a significant association within the neocortex where [ 11 C]SB207145 binding was 9% lower in S carriers compared to LL homozygotes. We did not find evidence for an effect of season or a season-by-5-HTTLPR interaction effect on regional [ 11 C]SB207145 binding. Our findings are consistent with a model wherein the 5-HTTLPR S allele is associated with relatively increased serotonin levels. These findings provide novel evidence supporting an effect of 5-HTTLPR status on serotonergic neurotransmission in adult humans. There were no indications of seasonal effects on serotonergic neurotransmission. © 2012 Elsevier Inc. All rights reserved. Introduction Serotonin (5-hydroxytryptamine, 5-HT) is a neuromodulator with significant effects on emotional behavior, including anxiety and sensitiv- ity to threat (Blier and de Montigny, 1998; Lucki, 1998). Genetic polymor- phisms that putatively affect serotonin signaling have been associated with affective disorders (e.g., depression and anxiety disorders) and as- pects of personality that confer risk for these disorders (Caspi et al., 2003; Fakra et al., 2009; Lemonde et al., 2003; Wankerl et al., 2010). A clearer understanding of how these genetic variants modulate aspects of serotonin signaling is critical for leveraging that genetic information to model underlying brain chemistry and brain function. In turn, this knowledge can be used to identify how underlying serotonin signaling and its effects on brain function may contribute to variability in person- ality and risk for affective disorders (Hariri, 2009). Imaging genetics using neuroreceptor binding positron emission tomography (PET) has emerged as an approach for evaluating the impact of genetic variants on molecular mechanisms in humans, in vivo. The 5-HTTLPR is a com- mon genetic variant within the gene (SLC6A4) coding for the serotonin transporter (5-HTT) where the ‘long’ (L) allele exhibits increased sero- tonin transporter (5-HTT) transcription in vitro relative to the ‘short’ (S) allele, putatively affecting 5-HT signaling (Lesch et al., 1996). As dis- cussed within a recent review of genetic sources of variability in seroto- nin signaling as measured with PET, there is evidence suggesting that 5- HTTLPR status is associated with individual differences in aspects of serotonin signaling (Willeit and Praschak-Rieder, 2010). Previous studies have reported reduced 5-HTT binding in S carriers with the PET radioligand [ 11 C]DASB(Kalbitzer et al., 2009; Praschak- Rieder et al., 2007; Reimold et al., 2007), though other studies, including one using the PET radioligand [ 11 C]McN5652, have reported no relation (Murthy et al., 2010; Parsey et al., 2006a). Additionally, the 5-HTTLPR NeuroImage 62 (2012) 130–136 ⁎ Corresponding author at: Copenhagen University Hospital Rigshospitalet, Neurobiology Research Unit, NRU 9201, Rigshospitalet, Blegdamsvej 9, Copenhagen O DK-2100, Denmark. Fax: +45 3545 6713. E-mail address: gmk@nru.dk (G.M. Knudsen). 1053-8119/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2012.05.013 Contents lists available at SciVerse ScienceDirect NeuroImage journal homepage: www.elsevier.com/locate/ynimg