The dopamine transporter/cocaine receptor (DAT) is the site at which cocaine experts rewarding/reinforcing effects and plays a central role in termination of dopamine neurotransmission. This gene is expressed most prominently in just those dopaminergic neurons most implicated in cocaine's psychomotor stimulant effects. We have isolated genomic clones of the human and mouse DAT genes that contain the 5' flanking sequences, and have begun work to identify the promoter for this gene, in order to provide means for selective overexpression of genes in just these dopaminergic neuronal populations. This work also allows identification and study of new gene polymorphisms that can serve as gene markers to enhance power of genetic analysis of DAT roles in neuropsychiatric disorders. Knowledge of the promoter and gene structure will allow transgenic mice that have modified dopamine transporters or modified expression of the genetic repertoire of dopaminergic neurons to be studied as potential animal models for human substance abuse disorders. Nearly complete human gene and partial mouse gene sequences have been identified and characterized. A short human DAT promoter sequence appears to drive expression of a reporter gene in dopaminergic neurons as well as non-dopaminergic neurons of the brain.
