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The Journal of Neuroscience, March 9, 2005, 25(10):2586-2590; doi:10.1523/JNEUROSCI.3769-04.2005

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BRIEF COMMUNICATION
A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT_1A Receptor Binding in Humans

Sean P. David,^1,3 * Naga Venkatesha Murthy,^2 * Eugenii A. Rabiner,^2,4 Marcus R. Munafó,¹ Elaine C. Johnstone,¹ Robyn Jacob,¹ Robert T. Walton,¹  and Paul M. Grasby² 

¹Department of Clinical Pharmacology, Cancer Research United Kingdom General Practice Research Group, University of Oxford, Oxford OX2 6HE, United Kingdom, ²Positron Emission Tomography Psychiatry, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom, ³Brown University Center for Primary Care and Prevention, Pawtucket, Rhode Island 02860, and ⁴Translational Medicine and Technologies, GlaxoSmithKline, Addenbrooke's Centre for Clinical Investigation, Cambridge CB2 2GG, United Kingdom

In humans, 5-HT_1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT_1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT_1A receptor expression in the living human brain was assessed using the 5-HT_1A-selective positron emission tomography (PET) ligand [¹¹C]WAY 100635. After the genotyping of 140 healthy volunteers to study population frequencies of known single nucleotide polymorphisms (SNPs) in the 5-HT_1A receptor gene, the influence of the common SNP [(-1018) C>G] on 5-HT_1A receptor expression was examined in a group of 35 healthy individuals scanned with [¹¹C]WAY 100635. In the PET group, we also studied the influence of a common variable number tandem repeat polymorphism [short (S) and long (L) alleles] of the 5-HT transporter (5-HTT) gene on 5-HT_1A receptor density. Whereas, the 5-HT_1A receptor genotype did not show any significant effects on [¹¹C]WAY 100635 binding, 5-HT_1A receptor binding potential values were lower in all brain regions in subjects with 5-HTTLPR short (SS or SL) genotypes than those with long (LL) genotypes. Although the PET groups are necessarily a small sample size for a genetic association study, our results demonstrate for the first time that a functional polymorphism in the 5-HTT gene, but not the 5-HT_1A receptor gene, affects 5-HT_1A receptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states.

Key words: serotonin; 5-HT_1A receptor; serotonin transporter; genetics; polymorphisms; positron emission tomography

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Received Sep 10, 2004; revised January 28, 2005; accepted January 29, 2005.

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