This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Dopamine is a neurotransmitter that has been implicated in the pathogenesis of several neuropsychiatric disorders, such as Parkinson's disease, schizophrenia, drug and alcohol abuse, Huntington's disease and attention-deficit hyperactivity disorder (ADHD). Dopamine transporter is a membrane-bound protein that reuptakes the released dopamine from the extracellular space back into presynaptic nerve terminals, and is the main regulator extracellular dopamine levels. Mice lacking the dopamine transporter have persistently elevated extracellular dopamine concentrations in the striatum, the main target region of dopaminergic innervation in the brain. In addition to displaying behavioral symptoms reminiscent of chronic psychostimulant abuse and schizophrenia, these mice sporadically develop progressive dyskinetic motor symptoms associated with striatal neurodegeneration resembling Huntingon's disease.
The aim of the proposed studies is to investigate in detail the consequences of sustained hyperdopaminergia on striatal neuronal anatomy. This will be accomplished by acquiring and comparing histological data using very high resolution magnetic resonance imaging (MRI) (at 9.4 T), conventional immunohistochemistry, and ultrastructural imaging modalities including electron microscopy. The results will help to understand the effects of chronically high striatal dopamine levels, and may lead to better understanding of neurobiology of schizophrenia, drug addiction and Huntington's disease.
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