The broad objectives of this study are to better understand the in vivo functioning of biogenic amines and the factors that modulate these pathways in a simple model system. These pathways are of enormous importance to human biology, movement disorders, and addictive states. We have evidence for a striking conservation in the types of behaviors that can be induced in flies by drugs affecting vertebrate dopamine receptors relative to their functional consequences in vertebrate animals. These behaviors can be induced both in decapitated adult flies, by direct application of drugs to the nerve cord, and also in living flies, by exposure to cocaine, an indirect agonist.
Specific aims i nclude (1) genetic selection for genes involved in cocaine responsiveness, selecting for altered cocaine resistance, and resistance to the sensitizing effects of repeated low dose exposure. Isolation of these genes will elucidate the biological pathways involved in these processes; (2) characterization of the mechnisms by which the amine pathways are modulated as a function of sex, time of subjective day, and cocaine sensitization. These studies will provide the basis for understanding how the mutants isolated in aim 1 lead to altered aminergic function; (3) identification of brain specific cis-regulatory elements of the Ddc gene. Using these elements, it will be possible to determine the behavioral roles of specific aminergic cell clusters.
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