COMT metabolizes dopamine and norepinephrine and others catechols. COMT plays an important role in the regulation of dopamine in the prefrontal cortex, where the dopamine transporter is less expressed.61,62 COMT knockout mice have increased levels of dopamine in this brain region.63,64 The COMT gene has two promoters that control the transcription of two different mRNAs and encode a soluble, cytoplasmic protein (S-COMT) and a membrane-bound form (MB-COMT) which—in humans—has 50 additional amino acid residues at the N-terminus. S-COMT predominates in most tissues, accounting for 95% of total COMT activity.65 In brain, where MB-COMT activity is much higher,66 this enzyme is located in the cell body, axons, and dendrites of cortical neurons.67 Val158Met is a common functional single nucleotide substitution of COMT,68 replacing methionine for valine at codon 158 of MB-COMT and at codon 108 of S-COMT. Via its effect on enzyme stability69,70 the Met158 allele is three- to fourfold less active.71 Because of its higher activity, the Val158 allele was predicted to lower dopamine level in the frontal cortex. Congruent with this hypothesis, the Val158 allele has been associated with
