Exposure to psychostimulants such as cocaine induces stereotypic, reflexive motor behaviors in vertebrate animal models of psychostimulant abuse, and in Drosophila melanogaster. Repeated doses of cocaine result in a phenomenon known as behavioral sensitization, which is defined as a long-lasting augmentation of drug responsiveness and is believed to be a correlative part of the addictive process. In Drosophila, the trace amine tyramine and its synthesizing enzyme, tyrosine decarboxylase (TDC), play important roles in the development of behavioral sensitization. Cocaine exposure significantly increases TDC enzyme activity in the brain in a time-dependent manner that parallels the development of sensitization. Additionally, in the mutant inactive (iav), which fails to develop sensitization and has significantly reduced levels of TDC, sensitization can be rescued by feeding tyramine The proposed research will seek to further identify the mechanisms underlying the up-regulation of TDC activity and to characterize how this up-regulation is involved in the development of cocaine sensitization in Drosophila. In order to attain this goal, I will develop tools to characterize the regulation of the Drosophila TDC and to identify its temporal and spatial distribution in the nervous system. By enhancing our understanding of TDC regulation and expression in Drosophila, I hope to provide clues regarding the basic mechanisms of cocaine sensitization in both the invertebrate and vertebrate brain.
| Hardie, Shannon L; Zhang, Jing X; Hirsh, Jay (2007) Trace amines differentially regulate adult locomotor activity, cocaine sensitivity, and female fertility in Drosophila melanogaster. Dev Neurobiol 67:1396-405 |
| Hardie, Shannon L; Hirsh, Jay (2006) An improved method for the separation and detection of biogenic amines in adult Drosophila brain extracts by high performance liquid chromatography. J Neurosci Methods 153:243-9 |
| Cole, Shannon H; Carney, Ginger E; McClung, Colleen A et al. (2005) Two functional but noncomplementing Drosophila tyrosine decarboxylase genes: distinct roles for neural tyramine and octopamine in female fertility. J Biol Chem 280:14948-55 |
