Rewarding/reinforcing effects of cocaine and amphetamines have been thought to be produced, at least in part, by blocking reuptake of dopamine by the dopamine transporter(DAT)and physiologically antagonizing the activities of the vesicular transporter VMAT2. DAT and VMAT2 are the sites that accumulate and sequester each of the dopamine selective toxins that produce the best current experimental models for Parkinson's disease. The DAT gene is expressed in dopaminergic neurons of the ventral midbrain, and serves as the only currently-available marker expressed almost exclusively by these cells, while VMAT2 is expressed in each monoaminergic cell group. During this year,we extended characterization of human DAT gene 5' flanking sequence and intronic polymorphisms in several normal and disease populations. We have made further progress toward defining the human polymorphisms and potential sites for imprinting in the human VMAT2 gene. Linkage disequilibrium in the DAT gene comes from two """"""""blocks"""""""". VMAT variations form striking haplotypes that define two alternative allelic forms of much of this gene that extend over more than 40 kb. Assessment of VMAT2 markers in individuals with a number of monoamine-related disorders reveals evidence for differential transmission to a second group individuals with narcolepsy studied during this year. During this year, we have enhanced information about the imprinting of this gene with two lines of evidence for highly-selective methylation of CpG residues in specific VMAT2 promoter cis acting elements found near its transcriptional initiation site, but not at adjacent sites. These studies continue to point to likely roles for transporter allelic variants in several sorts of human disorders.
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