The dopamine transporter/cocaine receptor (DAT) is the site at which cocaine exerts rewarding/reinforcing effects as well as playing a central role in termination of dopamine neurotransmission. Cloning of rat and human DAT CDNAS by Addiction Research Center scientists during the preceding FY provided primary sequence information and CDNA clones that facilitated isolation of genomic clones from rodent and human, development of polymorphic genetic markers, and application of these markers to human disorders hypothesized to involve dopaminergic system dysfunction or those treatable with dopaminergic agents. Screening of phage and cosmid genomic libraries from human and murine embryonic stem cells resulted in identification of several human and murine genomic clones of more than 20 kb (murine) and more than 9 kb (human), respectively. Attempts to drive expression of reporter genes with several constructs including the murine "promoter/enhancer" sequences were unrevealing, suggesting the possibility of strong cell- type specificity in the transporter's expression. Polymorphic genetic human transporter gene markers were used for analysis individuals with Tourette's syndrome and Parkinson's disease. No linkage between the DAT gene and Tourette's Syndrome was demonstrated in two large and 10 small kindreds; 5 centimorgans on either side of the DAT gene can be excluded by these analyses. No variation in the number of copies of the VNTR passed between generations has been detected in these families. No association between Parkinson's disease and DAT gene markers can be identified.
- National Institute on Drug Abuse
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