| Cocaine addiction is a devastating problem in our world today. Behavioral responsiveness to cocaine has been studied extensively in vertebrate models, yet still little is known about the molecular adaptations that occur in responses to cocaine, that lead to behavioral sensitization and addiction. Thus far there have been few studies using simple genetically tractable model systems to uncover the genes that are involved in these molecular pathways that ultimately lead to addiction. In this thesis, I pioneer the use of Drosophila melanogaster, a classic genetic system, to study the behavioral responses induced by cocaine. Drosophila responds to cocaine in a manner that is strikingly similar to that seen in vertebrate models. Furthermore, flies develop a sensitization or "reverse tolerance" to cocaine, which also parallels what is seen using vertebrate models, and may underlie the process of addiction in humans. From a genetic screen, I have isolated a mutant, inactive (iav), which shows normal initial responsiveness to cocaine, but fails to develop sensitization. These flies have low levels of the trace amine, tyramine due to a defect in the enzyme that converts tyrosine to tyramine, TDC. TDC is induced by cocaine in the Drosophila brain with, a time course that mirrors behavioral sensitization. Furthermore, feeding iav flies tyramine rescues behavioral sensitization. I have cloned a tyrosine decarboxylase gene, dTDC1, in Drosophila with high affinity and selectivity for tyrosine as a substrate. This is the first tyrosine decarboxylase cloned in an animal species, and may help us to discover an analogous gene in humans. Furthermore, the expression of this gene is increased in the heads of flies, six hours after cocaine exposure when compared to sham treated controls. Taken together, these studies have uncovered the importance of a new molecule, tyramine, in the development of sensitization to cocaine and have helped us to better understand the molecular mechanisms governing cocaine responsiveness and sensitization. |
