If this is successful, it will be followed by an intense investigation

on the psychoneuroendocrine consequences of such a genetic difference. Considering that 5-HTT knockout mice already exist,26-28 why is our investigation in rats so important? The following points encouraged us to follow our line of research: Constitutive knockout TWS119 cost models may be seen as all-ornothing paradigms, which impede any quest on the Inhibitors,research,lifescience,medical consequences of subtle (ie, <50%) differences in gene expression. Adaptive processes and features linked to the genetic background of the mouse strains are trivial limits of these models. The use of individuals that differ

in terms of the gene of interest, and also in other genes (as found using different strains), may help Inhibitors,research,lifescience,medical further define the regulatory links between the gene of interest and other unexpected genes. Some knockout models may be difficult to use due to their limited availability and/or the structures needed to breed them. In humans, the 5-HTT gene is highly polymorphic, as illustrated by allelic variations in the second intron Inhibitors,research,lifescience,medical and the upstream promoter region.29,30 Data regarding the promoter region suggest that polymorphisms in that region lead to differences in the 5-HT reuptake function of the 5-HTT30 Thus, the insertion/deletion of 14 and 16 copies of a 20- to 23-basepair repeat element leads to two promoter Inhibitors,research,lifescience,medical variants, the short and the long variants. When studied by means of reporter gene constructs and human lymphoblasts, the short variant was found to trigger, in a dominant manner, reductions in 5-HTT transcription and 5-HT reuptake, compared with the long variant.30 When examined ex vivo, however, peripheral and central 5-HTT densities and/or 5-HT reuptake did not always obey allelic variation.31 The initial Inhibitors,research,lifescience,medical finding that the short variant was associated with neuroticism30

substantiated the hypothesis that the 5-HTT plays a role in the susceptibility to mood disorders. Subsequent, studies both confirmed and refuted this initial finding; the diverging results could be accounted for by the low weight of the 5-HTT gene in some personality trait differences.32 The only currently available rodent models of 5-HTT Casein kinase 1 gene alterations are: Mice bearing a 100 % constitutive invalidation of their 5-HTT gene.26-28 Rats injected in their dorsal raphe with recombinant plasmids containing the sequence (overexpression) or a partial antiscnse (underexpression) sequence of the 5HTT gene.33 Rat sublines differing in terms of the platelet 5-HTT gene and protein expression as well as platelet 5-HT reuptake.