Neurons utilizing dopamine (DA) as a neurotransmitter constitute a rare neurochemical phenotype but nevertheless play an important role in regulating locomotion, motivation, cognition and hormone release. The DA transporter (DAT) is a plasma membrane transport protein that controls the spatio-temporal domains of DA neurotransmission by rapidly reaccumulating DA that has been released into the extracellular space. A wide spectrum of neurological and psychiatric disorders, including drug abuse, Parkinson's disease, schizophrenia, affective disorders, and attention deficit hyperactivity disorder is thought to involve DA systems and the DAT. The DAT is an important target for therapeutic and illicit drugs (e.g. methylphenidate, buproprion, amphetamine, and cocaine), and serves as the point of entry for DA-specific neurotoxins. DAT radioligand binding provides an in vivo measure of DA cell integrity and can be used to monitor the efficacy of therapeutic interventions in neurodegenerative disease.
The Aims of this project are to identify the silencing element(s) and cognate transcription factor(s) that repress transcription of the human dopamine transporter gene in non-dopaminergic cells, as well the mechanism by which the transcription factor nurrl activates human dopamine transporter gene transcription in dopamine neurons. It is likely that a greater understanding of the regulation of the DAT expression will impact the diagnosis and treatment of a number of neuropsychiatric disorders.
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