Role Of Rab10 In Methamphetamine Pathways Ofdrosophila Melanogaster

Objectives: Methamphetamine is a psychostimulant drug that acts on the dopaminergic system of the CNS. The mechanism of action of methamphetamine is poorly understood and abuse of the drug continues to be a worldwide problem. Methamphetamine is considered to be more addictive than heroin and is a significant contributor to crime. Methamphetamine also causes substantial detriments to health, including oral manifestations of rampant decay and severe wear of the dentition that results in a significantly decreased quality of life for the user. There are no drugs approved by the FDA for treatment of methamphetamine addiction and commonly used pharmacotherapies are insufficient.

Currently, most research carried out on methamphetamine uses rodent models. This project capitalizes on the ease of genetic manipulation and care of the fruit fly, Drosophila melanogaster, to investigate mechanisms of the drug.
Methods: Previous work has strongly implicated the dopaminergic system in the action of methamphetamine and we have recently shown that methamphetamine led to changes in the cellular distribution of the small GTP-binding protein Rab10 in rats. Taste-preference assays and activity monitoring experiments are being used here to identify changes in behavior and reaction to toxicity of methamphetamine on genetically manipulated strains of Drosophila.
Results: We have found that in Drosophila, methamphetamine led to an increase in behavioral activity that was blocked by pan-neuronal expression of a dominant-negative version of Rab10. We also found that Rab10 expression in neurons is required for the maximum toxicity of methamphetamine. Data presented here shows that Rab10 activity is required in serotonergic or dopaminergic neurons for methamphetamine toxicity.
Conclusions: Drosophila allows us to further investigate information gathered from our previous research on rodents in a simpler animal model. Our ultimate goal is to develop pharmacotherapies for specific inhibition of methamphetamine in order to treat addiction while limiting detrimental side effects.