The 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 Parkinsons 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 sell group. During this year, we completed characterization of each of the human DAT gene exonic polymorphisms, and several intronic polymorphisms in several normal and disease. We have made substantial progreaa toward defining each of the polymorphisms in each of the VMAT2 exons in smaller groups of humans. Each protein displays two amino acid sequence variants; conservative in DAT and less conservative in VMAT2. Findings of continued strengthening of associations between the 3untranslated region VNTR marker and ADHD in several studies have bee completmented by initial findings that a VMAT2 polmorphism is differentially distributed among amphetamine preferring and amphetamine nonpreferring human research volunteers. interest in regulatory region polymorphisms at this interesting locus. - cocaine amphetamine Parkinson's diseasse ADHD - Human Subjects: Interview, Questionaires, or Surveys Only
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