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If you see that any copyright content available there, you can report to eAction.Mutant forms of the enzyme catechol-O-methyltransferase (COMT) alter O-methylation levels, resulting in two categories of behavior: the hyperactive and the deficient form. The aim of this project is to determine the mechanism by which these two behavioral phenotypes arise, and to understand the effect of this polymorphism on the development of substance use disorder (SUD) and personality disorders (PD) in substance abusers. We have developed functional polymorphisms of the COMT gene, which are useful in understanding the mechanism by which COMT polymorphism confers differential activity in neurotransmitter systems involved in the pathogenesis of SUD and PD. To date, we have studied the effect of these polymorphisms on two neurochemical outcomes of catecholamine synthesis: O- methylation and DA synthesis. [unreadable] [unreadable] 1. In vitro studies indicated that the activity of COMT, specifically the Val(108) COMT allele, was associated with a reduction of catecholamine synthesis. This was accompanied by reduced O-methylation of 3,4-dihydroxyphenylalanine and reduced DA synthesis, resulting in lower levels of DA in the brain. This was studied in vivo in 229 subjects, including patients from addiction treatment programs. Further studies focused on the effect of COMT Val allele on axonal DA transport. Using high-resolution brain imaging in PET, we found that in healthy volunteers Val(108) COMT was associated with reduced brain DA levels and reduced striatal DA uptake. Thus, the Val(108) allele has opposite effects on DA synthesis and transport, possibly explaining its susceptibility to SUD. Because COMT Val is reduced also in PD, we have begun to study whether the presence of a COMT Val allele alters striatal DA uptake in PD patients, and preliminary results suggest that this is the case. [unreadable] [unreadable] 2. Although the Val allele is associated with reduced DA synthesis and transport, catecholamines are not reduced in the brains of Val carriers. To understand the basis for this, we obtained measurements of activity of COMT Val, Met, and 138 other novel polymorphisms using in

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