Flies display many of the behaviors observed in mammals after both, acute and chronic exposure to ethanol. Flies display signs of hyperactivity, incoordination, followed by sedation and hypnosis. In addition, flies develop tolerance to ethanol and undergo 'withdrawal-like' symptoms upon ethanol removal. We have developed assays that allow the quantification of these behaviors, and have isolated mutants that respond abnormally to ethanol exposure. Several of the genes disrupted by these mutations and the pathways in which they function are currently being investigated. We are using similar approaches to study the mechanisms that regulate the responses to psychostimulants such as cocaine, nicotine, and phencyclidine.

In addition to defining drug-induced behaviors and their genetic control, we have begun to map the neuroanatomical sites of drug action and their relation to specific behaviors. For this purpose we are using targeted expression of neurotoxins in specific brain regions. Integrating the information gained from behavioral, genetic, molecular, and neuroanatomical analyses will help us gain an understanding of drug-induced behaviors in flies and, eventually, in mammals.

Recently, we have begun the process of transferring the information gained from Drosophila to mammals. Specifically, we have selected for further study a group of mouse genes that are structurally and functionally related to Drosophila genes defined in our genetic screens. The mouse genes will be disrupted by gene-targeting or by RNA interference, and their role in drug-related behaviors will be tested using well-established behavioral paradigms.