The human serotonin transporter (5-HTT) gene is one of the most extensively studied in psychiatry. A functional polymorphism in the promoter region of the 5-HTT gene (5-HTTLPR) has been associated with several psychiatric disorders as well as anxiety-related personality traits. In search of a mechanistic understanding of the functional implications of 5-HTTLPR, the influence of this polymorphism on regional 5-HT1A receptor density has previously been examined in two positron emission tomography (PET) studies in humans, yielding, however, contradictory results. In the present study, 54 control subjects were examined with [11C]WAY 100635 PET and a battery of cognitive tests. Regional binding potential (BP) of [11C]WAY 100635 to 5-HT1A receptor was calculated for the dorsal raphe nuclei, the hippocampus, the anterior cingulate, the insula, the temporal cortex and the frontal cortex. The influence of 5-HTTLPR genotype on regional 5-HT1A BP and cognitive performance was investigated. No differences in 5-HT1A receptor density between carriers and non-carriers of the S allele were found. Thus, we could not replicate any of the previously reported associations between 5-HTTLPR and 5-HT1A density. There was, however, a highly significant association between 5-HTTLPR genotype and performance in Wisconsin Card Sorting Test; carriers of the S allele had a superior performance compared to the LL carriers. These observations suggest that functional implications of the 5-HTTLPR polymorphism are not likely to be mediated by differences in 5-HT1A expression levels and that other biomarkers must be considered for future investigations at phenotype level.

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Receptors of the 5-HT2C subtype are assumed to be involved in the influence of serotonin on food intake. A polymorphism in the coding region of the gene for this receptor, resulting inData from family and twin studies suggest that genetic factors may contribute to the development of eating disorders such as anorexia nervosa (AN) (Holland et al. 1988;Gorwood et al. 1998;Lilenfeld et al. 1998;Bulik et al. 2000;Strober et al. 2000;Kortegaard et al. 2001). As yet, no consistent findings regarding associations between specific candidate genes and eating behavior have however been reported.Serotonin appears to exert an important inhibitory influence on food intake in experimental animals, and serotonin-facilitating compounds are known to reduce food intake also in humans (Leibowitz and Alexander 1998). An involvement of serotonin in the pathophysiology of AN gains support from the observations of altered cerebrospinal fluid serotonin metabolite levels (Gillberg 1983;Kaye et al. 1984;Kaye and Weltzin 1991) and abnormal hormonal responses to serotonergic probes (Brewerton and Jimerson 1996;Goodwin et al. 1989;Hadigan et al. 1995;Monteleone et al. 1998;Ward et al. 1998; see also O'Dwyer et al. 1996) in AN subjects, as well as from the fact that treatment with serotonin reuptake inhibitors may prevent relapse in weight-restored AN subjects Mayer and Walsh 1998;Kaye et al. 2001 NO . 6 Pharmacological studies in rats (Dourish et al. 1989;Kennett and Curzon 1991), and experiments using knockout mice (Tecott et al. 1995), suggest that the influence of serotonin on food intake is partly mediated by 5-HT2C receptors. This notion gains support from the observation that weight gain is a common side-effect of antidepressant and antipsychotic drugs acting as antagonists at 5-HT2C receptors, and by preliminary data suggesting that 5-HT2C-blocking compounds may be effective for the treatment of AN (Goldberg et al. 1979;Halmi et al. 1986;La Via et al. 2000). Of interest in this context is also the finding that dieting may increase 5-HT2C receptor responsiveness in humans (Cowen et al. 1996). Previous studies have suggested that AN may be associated with a polymorphism in the gene coding for another 5-HT2 receptor-the 5-HT2A subtype-but subsequent studies on this issue have yielded conflicting data (Collier et al. 1997;Ziegler et al. 1999). With respect to a possible relationship between the 5-HT2C receptor gene and AN, the literature is as yet sparse.The 5-HT2C receptor gene is located on the X chromosome, at q24, and contains a single nucleotide polymorphism, resulting in a cysteine to serine substitution at position 23 (cys23ser) of the receptor (Lappalainen et al. 1995). The aim of this study was to examine the possible association between this polymorphism and weight loss (regardless of underlying diagnosis) in teenage girls. METHOD SubjectsThe original purpose of this investigation was to establish the rate of AN in 16-year-old girls in Göteborg, and to compare AN girls and age-, sex-, and school-matched controls with respec...