This is a request for competitive renewal of an ADAMHA Research Scientist Award to support the continuation of studies on the plasticity and function of central catecholaminergic systems. The focus of the work has shifted, for the moment, from norepinephrine to dopamine systems, largely because of the impression specificity of the effects of MPTP (1-methyl4-phenyl 1,2,5,6-tetrahydropyridine). This neurotoxin produces behavioral changes in human and non-human primates which closely resemble Parkinson's disease. Its effects are associated with a substantial loss of dopamine neurons from the substantia nigra, decreased dopamine function assessed biochemically, and the classical signs of termor, motor inhibition, muscular rigidity, incoordination and behavioral impairment. This syndrome provides a useful model for studying the functional, biochemical, and morphological sequelae of the transplantation of fetal mesencephalic tissue containing dopamine neurons. This program proposes, therefore, to continue with six basic experiments: (1) to determine the effects of MPTP treatment and fetal neural transplantation on neuronal morphology, dopamine biochemistry, and behavior, during longer time periods in monkeys; (2) to examine the function of these grafts and their integration with the host, using morphological, electron microscopic, biochemical, and pharmacological techniques, and behavioral methods; (3) to examine possible mechanisms of improvement addressed by experimental destruction of successful grafts; (4) to determine whether long-acting dopamine implants reproduce the effects of grafts; (5) to improve graft methods by studying the development of fetal dopamine systems in the African green monkey and examining ways to improve the techniques for neural transplantation in primates; and (6) to improve graft function by the addition of co-grafts and other factors. These studies may lead to improved understanding of the plasticity and function of dopaminergic systems and human diseases associated with alterations in dopamine function, such as Parkinson's disease, manic-depressive illness, and schizophrenia.
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