Association between triallelic polymorphism of the serotonin transporter and [ 18 F] MPPF binding potential at 5-HT 1A receptors in healthy subjects Amélie Lothe a,b , Claudette Boni c , Nicolas Costes d , Philip Gorwood c , Sandrine Bouvard a , Didier Le Bars d , Franck Lavenne d , Philippe Ryvlin a,b,e, ⁎ a CTRS-IDEE, Lyon, France b INSERM U821, University Claude Bernard Lyon 1, INFL, Lyon, France c INSERM U675, Faculté Xavier Bichat, University Paris VII, Paris, France d CERMEP imagerie du vivant, Lyon, France e Department of Functional Neurology and Epileptology, Hospices Civils de Lyon, France abstract article info Article history: Received 24 November 2008 Revised 11 April 2009 Accepted 15 April 2009 Available online xxxx Previous [ 11 C]WAY100-635 PET studies have demonstrated that the short (S) and long (L) alleles of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) were associated with distinct patterns of 5-HT 1A receptor distribution in human. However, these studies reported discordant findings and did not take into account the recent description of two functional variants of the L allele (L A /L G ). To further explore this issue, we investigated the triallelic functional polymorphism of the 5-HTTLPR in 38 healthy volunteers who underwent a [ 18 F]MPPF PET study of 5-HT1A receptors. We used a simplified reference tissue model to generate parametric images of [ 18 F]MPPF binding potential (BP ND ), and compared these data among the different genotypes using statistical parametric mapping and region of interest of the raphe nuclei. Homozygote carriers of the S allele demonstrated greater [ 18 F]MPPF BP ND than carriers of the L A allele, but this association was only found in women. Differences in [ 18 F]MPPF BP ND between women with and without L A allele were observed over large clusters encompassing the right and left temporal lobes, cingulate and perisylvian regions, as well as the right precuneus and frontal dorso-lateral cortex, and the left orbitofrontal cortex. In contrast, no difference was found between groups in the raphe nuclei. The greater [ 18 F]MPPF BP ND observed in women homozygote carriers of the S allele could either reflect a greater 5-HT1A receptor density or a lower extracellular concentration of 5-HT. Our data suggest that any future PET studies of 5-HT1A receptors should incorporate the 5-HTTLPR polymorphism status of the population studied. © 2009 Elsevier Inc. All rights reserved. Introduction Serotonin (5-hydroxytryptophan, 5-HT) is a modulating neuro- transmitter of the central nervous system involved in a large spectrum of physiological activities (Lucki, 1998; Barnes and Sharp, 1999) including sleep, locomotion, eating, memory, endocrine modulation, and sexual behaviour. Furthermore, the serotoninergic system is altered in multiple diseases such as depression (Drevets et al., 2007; Maes and Meltzer, 1995), migraine (Lothe et al., 2008a), epilepsy (Didelot et al., 2008; Lothe et al., 2008b; Merlet et al., 2004), Alzheimer's disease (Truchot et al., 2008; Buhot et al., 2000), eating disorders (Hainer et al., 2006), anxiety (Gross et al., 2002), schizophrenia (Iqbal and van Praag, 1995) and autism (Burgess et al., 2006; Chugani, 2004). The serotonin transporter (5-HTT) and the 5-HT 1A receptors predominantly modulate serotonin concentration and play a pivotal role in the regulation of serotoninergic neurotransmission (Lesch and Mössner, 1998; Blakely et al., 1994). 5-HT 1A receptors are mostly expressed in neurons, either as heteroreceptors when located in target regions of 5-HT neurons with a particularly high concentration in limbic areas, or as autoreceptors on the soma and dendrites of 5-HT neurons in raphe nuclei, where they exert negative feedback on the serotoninergic neuron firing rate and serotonin release (Richer et al., 2002; Weissmann-Nanopoulos et al., 1985). The serotonin transporter is a complex plasma membrane protein expressed in serotoninergic neurons that is involved in the re-uptake of extracellular serotonin from the synapse (Rudnick, 2006). The serotonin transporter (5-HTT) is encoded by the SLC6A4 gene located on chromosome 17, at 17q11.2. A 44-base pair insertion/deletion polymorphism in the 5′ flanking regulatory region of the serotonin transporter (5-HTT gene-linked polymorphic region; 5-HTTLPR) with a short (S) and a long variant (L), has been described (Heils et al., 1996; Lesch et al., 1996). The S allele is NeuroImage xxx (2009) xxx–xxx ⁎ Corresponding author. Unité 301, Hôpital Neurologique, 59 Bd Pinel, 69003, Lyon, France. E-mail address: philippe.ryvlin@chu-lyon.fr (P. Ryvlin). YNIMG-06182; No. of pages: 11; 4C: 1053-8119/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2009.04.067 Contents lists available at ScienceDirect NeuroImage journal homepage: www.elsevier.com/locate/ynimg ARTICLE IN PRESS Please cite this article as: Lothe, A., et al., Association between triallelic polymorphism of the serotonin transporter and [ 18 F]MPPF binding potential at 5-HT 1A receptors in healthy subjects, NeuroImage (2009), doi:10.1016/j.neuroimage.2009.04.067