Genetic and Pharmacological Approaches to Study Drugs of Abuse in Drosophila

Linus T.-Y. Tsai, Roland J. Bainton, Monica S. Moore, Carol M. Singh, Henrike Scholz, and Ulrike Heberlein

Department of Anatomy, Anesthesia, and Neurology, Programs in Neuroscience and Developmental Biology, University of California at San Francisco, San Francisco, CA 94143-0452

Sensitivity to ethanol and the development of tolerance and dependence are influenced substantially by genotype in humans and rodents. In addition, evidence is emerging from studies in animal and cellular model systems indicating that the effects of ethanol on a variety of cellular functions are mediated by changes in specific proteins. Thus, Drosophila, an organism readily accessible to genetic and molecular analysis should prove useful in establishing missing links between genes and behavior. We have found that adult flies display many of the behaviors observed in humans after both acute or chronic exposure to ethanol vapor. Flies display signs of hyperactivity, incoordination, followed by sedation and hypnosis. In addition, flies develop tolerance after single and multiple ethanol exposures. We are carrying out genetic screens designed to isolate mutations that cause altered sensitivity to ethanol intoxication or that impair or enhance development of tolerance. Sensitivity to intoxication is quantified in an 'inebriometer', a device that measures postural control. Tolerance is defined as a decrease in this sensitivity caused by previous ethanol exposure. The behavioral and molecular characterization of mutations that alter ethanol sensitivity and tolerance will be described.

In mammals, a common property of drugs of abuse is their ability to facilitate dopamine (DA) release in specific brain regions involved in reward and motivation. This increase in DA levels is believed to act as a positive reinforcer and to mediate some of the acute drug responses such as locomotor activation. We have found that DA plays a role in the responses of Drosophila to cocaine, nicotine, and ethanol. We have developed a quantitative behavioral assay, based on negative geotaxis, that measures the effect of psychostimulants on fly behavior. Acute responses to cocaine and nicotine are blunted by pharmacologically-induced reductions in DA levels. Co-administration of cocaine and nicotine shows a high degree of synergy, consistent with an action through convergent pathways. Normal DA levels are also required for ethanol-induced locomotor activation, but not sedation. We conclude that in Drosophila, as in mammals, dopaminergic pathways play a role in modulating behavioral responses to multiple drugs of abuse.