Both COMT, as a catecholamine catabolizing enzyme, and the DA transporter, DAT1, work together to clear extracellular DA from the SB216763 synaptic cleft. In doing so, they

regulate synaptic DA concentrations in the brain mainly in cortical and subcortical regions. A contribution of both the COMT and the DAT1 polymorphisms to the activity of the DA system and an interaction (epistasis effect) of these genes is quite likely, at least from a pharmacological Inhibitors,research,lifescience,medical viewpoint. In humans, the COMT gene contains a functional nonsynonymous single nucleotide polymorphism (SNP), a guanine to adenine transition in codon 158 of the COMT gene located at the q11 band of human chromosome 22 (rs#4680). The substitution of the amino acid Val by Met results in decreased thermostability of the protein leading to Inhibitors,research,lifescience,medical a three- to fourfold reduced COMT enzyme activity at physiologically relevant temperatures. The COMT alleles are codominant with three genotypes possible: carriers of the Val/Val genotype have highest, carriers of the Met/Met genotype have lowest, and heterozygotes (Val/Met genotype) have intermediate levels of COMT enzyme activity (Lachman et al. 1996; Chen et al. 2004; Weinshilboum et al. 1999). Consistently, the number of Met alleles is positively related to prefrontal DA levels (Tunbridge et al. 2006). The involvement of the COMT Val158Met polymorphism in emotional processing is supported by numerous association studies relating

the Met Inhibitors,research,lifescience,medical allele or the Met/Met Inhibitors,research,lifescience,medical genotype to anxiety disorders (Enoch et al. 2003; Domschke et al. 2004; McGrath et al. 2004; Woo et al. 2004; Olsson et al. 2005; Montag et al. 2008), anxiety-related traits including high neuroticism, and low sensation seeking and low extraversion (Reuter and Hennig 2005; Stein et al. 2005; Lang et al. 2007) and obsessive-compulsive disorder (Pooley et al. 2007). A diminished stress resilience and emotional regulation for the Met allele (Goldman et al. 2005) is in line with an association with increased pain sensitivity (Zubieta et al. 2003). In addition, Inhibitors,research,lifescience,medical the Met allele is associated

with the onset of mood disorders after exposure to adverse life events (Mandelli et al. 2007). These findings suggest that the COMT Val158Met polymorphism and especially the Met/Met genotype leads to increased predisposition to emotional Terminal deoxynucleotidyl transferase disorders, with anxiety and depression as the most common ones. However, it must be noted that despite of this high convergent validity that relates the Met allele to NEM and the Val allele to PEM, there are also some studies reporting conflicting results. The human dopamine transporter (DAT1/SLC6A3) gene localized on chromosome 5p15.3 contains a 40 base pair (bp) variable number of tandem repeats (VNTR) polymorphism in its 3′-untranslated region (3′UTR) with repeat numbers ranging from 3 to 11. The two most frequent alleles in the population are the nine- and 10-repeat (9R and 10R) alleles (Vandenbergh et al. 1992).