Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia Tomas Furmark a, * , Maria Tillfors a,b , Ha ˚kan Garpenstrand c , Ina Marteinsdottir d , Bengt La ˚ngstro ¨m e , Lars Oreland c , Mats Fredrikson a a Department of Psychology, Uppsala University, Uppsala, Sweden b Department of Behavioral, Social and Legal Sciences, O ¨ rebro University, O ¨ rebro, Sweden c Department of Neuroscience, Pharmacology, Uppsala University, Uppsala, Sweden d Department of Neuroscience, Psychiatry, Uppsala University, Uppsala, Sweden e Uppsala Imanet AB, University Hospital, Uppsala, Sweden Received 10 December 2003; received in revised form 22 January 2004; accepted 26 February 2004 Abstract A functional polymorphism in the promoter region of the human serotonin transporter (5-HTT) gene has been related to negative affect and amygdala activity. We studied amygdala activation during social anxiety provocation in relation to affective ratings and 5-HTT genetic variation. [H 2 15 O]positron emission tomography was used to estimate amygdala blood flow during private and public speaking (baseline and anxiety conditions) in 17 patients with social phobia. Genotyping identified patients with long and short alleles in the promoter region of the 5-HTT. Individuals with one or two copies of the short allele exhibited significantly increased levels of anxiety-related traits, state anxiety, and enhanced right amygdala responding to anxiety provocation, compared with subjects homozygous for the long allele. Thus, 5-HTT genetic variation was associated with symptom severity and amygdala excitability in social phobia. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Anxiety; Emotion; Genotyping; Amygdala; Positron emission tomography; Serotonin transporter; Social phobia There is abundant evidence that mood and anxiety are at least partly modulated by serotonergic neurotransmission [8]. Disturbances in the serotonergic system are likely to be involved in the pathogenesis of disorders of the affective spectrum. The reuptake of serotonin in the synapse is mediated by the serotonin transporter (5-HTT). In the untranslated regulatory region upstream of the gene encoding the 5-HTT, there is a 44 base pair insertion/ deletion gene-linked polymorphic region divided into alleles inducing either low or high transcriptional activity, i.e. short or long alleles [12]. The presence of two long alleles, rather than one or two copies of the short allele, is associated with an increased serotonin reuptake [14]. This difference appears to have behavioral consequences, in particular for anxiety- or depression-related personality traits and other characteristics related to negative affect. Initial studies suggested that the presence of the short allele was associated with higher levels of neuroticism [9,14], harm-avoidance [16] and other anxiety-related scales [9,14, 16]. The short allelic variant has also been related to fear conditionability [7] and affective illness [3,17]. Allelic variation in functional expression of the 5-HTT may thus be a susceptibility factor for developing anxiety and/or mood disorders. On the other hand, several attempts to replicate findings on 5-HTT promoter polymorphism and psychopathology have been negative, particularly regarding the association between the short allele and neuroticism (cf. Ref. [6]). Studies of psychiatric anxiety conditions have not demon- strated a link between the 5-HTT gene and panic disorder [10] or social phobia [19]. Evidence is inconclusive also with regard to depression [15]. It is possible that variations in the 5-HTT gene are not directly associated with anxiety or mood disorders, although the 5-HTT gene may interact with environmental conditions thereby affecting the indivi- dual’s vulnerability for developing psychopathological 0304-3940/03/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2004.02.070 Neuroscience Letters xx (2004) 1–4 www.elsevier.com/locate/neulet * Corresponding author. Department of Psychology, Uppsala University, Box 1225, SE-751 42 Uppsala, Sweden. Tel.: þ 46-18-471-21-53; fax: þ 46-18-471-21-23. E-mail address: tomas.furmark@psyk.uu.se (T. Furmark). NSL 20946—21/4/2004—10:26—LORRAINEOB—20946— MODEL 5 – br,ed ARTICLE IN PRESS