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 each of the human DAT gene exonic and intronic polymorphisms in several normal and disease populations and characterized and identified polymorphisms in several kb of putative DAT genomic regulatory sequence. We have made further progreaa toward defining the human polymorphisms in each of the VMAT2 exons and in more than 20 kb of 5' flanking sequence. Linkage disequilibrium among the DAT variants falls off over distances of ca 10-20 kb. However, the VMAT variations form striking haplotypes that define two alternative allelic forms 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 individuals with narcolepsy, in a pattern suggesting possible imprinting of this human gene. We are thus reapproaching findings in other disease samples where it is possible to determine parent of origin of each VMAT2 allele. These studies complement previous reproducible findings of association between the 3'untranslated region VNTR marker and ADHD, and point to likely roles for transporter allelic variants in several sorts of human disorders.
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