The long-term objective of this project is to elucidate the molecular and cellular biology of the dopamine transporter (DAT), a plasma membrane protein thought to control synaptic levels of the neurotransmitter dopamine. Distinct alterations in DAT expression have been reported in Parkinson's disease, Alzheimer's disease, normal aging, schizophrenia. Tourette's syndrome, Lesch-Nyhan disease, and drug abuse. Another striking feature of the DAT is the extraordinary tissue specificity of expression. We have recently sequenced a portion of the human DAT gene and identified a number of potential regulatory elements. A detailed functional analysis of the DAT promoter is clearly warranted but currently hindered by a number of practical and technical considerations. The proposed experiments will establish the methodology for particle-mediated DNA transfections of organotypic rat midbrain slice cultures, such that authentic DA neurons can be transfected with DAT gene constructs and rapidly analyzed. DAT gene sequences conferring tissue specificity of expression and cocaine responsiveness will be identified. An understanding of the regulation of the DAT gene may shed light on a number of neuropsychiatric disorders.
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