Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain
Introduction
The neuronal serotonin transporter (5-HTT) plays a critical role in the regulation of serotonin (5-HT) neurotransmission and drugs targeting the 5-HTT such as selective serotonin re-uptake inhibitors (SSRIs) are used extensively in the management of mood and anxiety disorders. The gene encoding the 5-HTT has a number of polymorphic variants and one in the 5-HTT-linked promoter region (5-HTTLPR) is composed of a short (S) and long (L) version which results in differential transcription of the 5-HTT in vitro, with the L form being associated with higher 5-HTT expression levels (Lesch et al., 1996). More recently the 5-HTTLPR has been shown to exist in a triallelic form because the L allele itself has two functional variants (LA and LG) with the LG form exhibiting similar levels of 5-HTT expression in vitro as the S allele (Hu et al., 2006).
It is important to determine whether 5-HTTLPR genotype affects expression of the 5-HTT in the human brain as this would have important implications for the role of individual variation of the 5-HTTLPR in the pathophysiology of emotional disorders and the effects of antidepressant treatment. It is possible to approach this question using positron or single photon emission tomography (PET or SPET) in conjunction with ligands designed to bind specifically to the 5-HTT.
The results to date of these investigations have been inconsistent probably as a consequence of relatively modest sample sizes and ligands of varying specificity for the 5-HTT. Using [123I]-βCIT with SPET in 96 healthy subjects, van Dyck et al. (2004) reported higher 5-HTT binding in brainstem and striatum among carriers of the SS genotype, but this result was not confirmed in two smaller investigations also using [123I]-βCIT (Jacobsen et al., 2000, Willeit et al., 2001). A limitation of studies with [123I]-βCIT is that this ligand has similar affinity for the dopamine transporter and the 5-HTT and it is not possible to image the 5-HTT in cortical brain areas relevant to emotional regulation such as anterior cingulate cortex and limbic structures. However, two more recently developed PET ligands, [11C] McN5652 and [11C] DASB, allow specific quantification of the 5-HTT in these brain areas. Once again the data regarding the effect of 5-HTTLPR genotype are contradictory. Using [11C] McN5652, Parsey et al. (2006) found no effect of the triallelic polymorphism on 5-HTT binding in 42 healthy subjects and 25 acutely depressed patients. However, Praschak-Rieder et al. (2007) using [11C] DASB in 43 healthy subjects reported increased 5-HTT in putamen specifically in those with an LA/LA genotype. Reimold et al. (2007), showed a similar effect in midbrain in 19 healthy volunteers with LA/LA genotype (Reimold et al., 2007).
As a 5-HTT ligand, [11C] DASB compares favourably to [11C](+)McN 5652 in terms of the ratio of specific to non-specific binding. The aim of the present study was therefore to use [11C] DASB in conjunction with PET to assess the role of 5-HTTLPR polymorphisms on the availability of brain 5-HTT to [11C] DASB binding, in the largest group of healthy volunteers, using a full metabolite corrected arterial input function and graphical analysis to quantify regional activity.
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Participants
The study was approved by the Research Ethics Committee at Hammersmith Hospital, London, and the Administration of Radioactive Substances Advisory Committee (ARSAC), UK. All participants gave written informed consent for the study. We recruited 63 healthy European caucasian men (mean ± SD age 38.5 ± 11.1 years) with no current or past psychiatric history or substance misuse problems. Subjects with any serious medical or neurological (current or past) illness, alcohol or illicit substance dependence
Results
Biallelic genotyping of the 5-HTTLPR revealed that of the 63 participants, 10 (16%) were SS, 35 (56%) were SL and 18 (28%) were LL (Table 1). The frequencies of the triallelic genotypes are shown in Table 2. These frequencies did not differ significantly from Hardy–Weinberg equilibrium (Chi squared = 1.054, and p = 0.3047).
As reported previously the binding of [11C] DASB was most concentrated in raphe with moderate densities apparent in several other brain regions including putamen, thalamus,
Discussion
Our cross-sectional data in a large group of healthy volunteers, suggest that polymorphic variation in the 5-HTTLPR does not alter the expression of the 5-HTT in adult human brain as measured by [11C] DASB binding potential. The findings remained the same whether the 5-HTTLPR was classified on a biallelic or triallelic basis. We included among the brain regions examined, areas that previous reports have implicated as showing an effect of 5-HTTLPR genotype on 5-HTT expression, for example,
Acknowledgments
This study was funded in part by the Medical Research Council, UK and GlaxoSmithKline. The authors thank the staff at Hammersmith Imanet (Rainer Hinz, Subrata Bose, Andrew Blyth, Hope McDevitt, Andreanna Williams, Safiye Osman, Noora Ali, Sam Tagoe, Shaun Creasey, and Leonard Schnorr) for the technical expertise they provided and Daniele Turner for help with recruitment.
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These authors have equally contributed to this work.