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Perspectives on Neuroscience and Behavior

In humans, the long allele, compared to the short allele, of the serotonin (5HT) transporter (5HTT) promotor polymorphism has been shown to result in a twofold greater serotonin uptake in cultured human lymphoblast cell lines and similar sized increases in serotonin transporter binding levels in the brain. Serotonin is involved in the expression of normal fear as well as pathological anxiety, and drugs that selectively block serotonin reuptake (selective serotonin uptake inhibitors) are effective in the treatment of depression and several anxiety disorders. Animal and human clinical studies have shown that both normal fear and pathological anxiety involve the amygdala. Now, it has been shown using functional magnetic resonance imaging in 28 subjects that the 14 individuals who were homozygous or heterozygous for the short form of the 5HTT allele demonstrated greater right amygdala activity in response to viewing fearful faces in comparison to the individuals homozygous for the long allele (Hariri and others 2002). The short allele individuals also had larger responses within the distributed perceptual network, including the right posterior fusiform gyrus, but they did not have different accuracy or reaction time in the fear-generating task and they did not have a different brain activity to a working memory task. There also were no differences between the long and short allele groups on the assessed anxiety or fear-related behavioral measures, which suggests that the imaging method utilized is a more sensitive assay of the genotype than behavioral measures. A paradox remains to be resolved, however, between the findings of presumed increased synaptic serotonin in the anxiety-prone individuals with the short allele and the antianxiety effects of selective serotonin reuptake inhibitors, which markedly increase synaptic serotonin levels even more. If anxiety is related to low synaptic serotonin levels, then the individuals with the long allele should be more anxious. Because this is not the case, more research will be required to unravel this problem.