Identification of molecular and neuroanatomical substrates regulating acute cocaine sensitivity in Drosophila melanogaster

Susceptibility to drug addiction depends on a complex interaction between genetic and environmental factors. Studies of mammals have identified molecular substrates, neurochemical systems, and brain regions that mediate some of the actions of drugs of abuse. However, there still remains a fundamental lack of knowledge about what causes addiction and an even greater lack of insight into treatment options for patients afflicted by this disease.; The fruit fly Drosophila melanogaster has been a useful system for the genetic dissection of many developmental processes. Most of the genes and molecular pathways discovered in flies have structural or functional homologs in humans, revealing evolutionary conservation of developmental and physiological processes. More recently, Drosophila has been advanced as a model system for dissecting the mechanisms that regulate behavioral responses to drugs of abuse, including cocaine. Several of cocaine's most characteristic properties have been recapitulated in flies, including the induction of behaviors similar to those observed in mammals and the development of behavioral sensitization to repeated cocaine administration. We developed simple, high-throughput assays to measure the behavioral effects of cocaine in flies. Paralleling mammalian findings, we show a common role for dopaminergic systems in mediating actions of cocaine and other drugs of abuse.; A genetic screen for mutants with altered cocaine sensitivity identified a role for the Drosophila Lim-only (Lmo) gene in the modulation of cocaine behaviors. Lmo mutants reveal a novel role for the Drosophila circadian pacemaker neurons (LNs) in modifying cocaine sensitivity. Reduced Lmo expression in the LNs increases cocaine sensitivity, while increased Lmo expression in the LNs reduces cocaine sensitivity. Furthermore, wild-type Lmo expression is necessary for robust circadian locomotor rhythms, suggesting a general role for Lmo in LN function. Genetic ablation or functional silencing of LNs reduces cocaine sensitivity, indicating that LN activity normally acts to increase cocaine sensitivity. Lastly, we show that the LNs' role in modulating cocaine actions is functionally and genetically separable from their role in modulating circadian rhythmicity. Together, these studies demonstrate Drosophila as a genetically tractable model organism in which to identify and characterize molecular and neurobiological substrates of drug action.