Associate editor: B.L. RothDrosophila melanogaster neurobiology, neuropharmacology, and how the fly can inform central nervous system drug discovery
Introduction
Central nervous system (CNS) drug discovery in the post-genomic era is rapidly evolving. Older empirical methods are giving way to newer technologies that include bioinformatics, structural biology, genetics, and modern computational approaches. These newer methods have so far had limited success, however, in part because target identification and validation represent real obstacles to their efficient use. With all these new tools available, the questions one must ask are, “What do we do with them? How can we best use them?” Everyone seems to agree that they represent powerful technologies, if only we can deduce how best to employ them.
In the search for new medical therapies, and in particular treatments for disorders of the CNS, there has been increasing recognition that identification of a single biological target is unlikely to be a recipe for success; a broad perspective is required. Systems biology is one such approach, and has been increasingly recognized as a very important area of research, as it places specific molecular targets within a context of overall biochemical action. Understanding the complex interactions between the components within a given biological system that lead to modifications in output, such as changes in behavior or development, may be important avenues of discovery to identify new therapies.
One avenue to drug discovery that holds tremendous potential is the use of model genetic organisms such as the fruit fly, Drosophila melanogaster. Model genetic organisms represent intact living systems where complex biological patterns and processes can be readily examined. Furthermore, the similarity between mode of drug action, behavior, and gene response in D. melanogaster and mammalian systems, combined with the power of genetics, have recently made the fly a very attractive system to study fundamental neuropharmacological processes relevant to human diseases. While the fly is quite similar in many respects to vertebrates, the reader should keep in mind that for each system studied there are likely key differences that need to be taken into account when using the fly as a model. The promise that the use of model organisms such as the fly offers is speed, high throughput, and dramatically reduced overall costs that together should result in an enhanced rate of discovery.
This review, therefore, will serve as a basic primer on Drosophila neuropharmacology. There is no intent to present a comprehensive discussion of all of the important or attractive features of Drosophila as an organism. This review is designed for investigators who have primarily focused on mammalian systems and wish to gain a perspective on how the fly can either complement or even supplant drug discovery research underway in their laboratories. This review should be particularly appealing to those in the pharmaceutical industry faced with the current difficulties of target identification and validation.
The first sections of the review will provide an introduction to basic fly CNS development and physiology, with emphasis on parallels to human systems. Descriptions of fly neurotransmitter circuits relevant to CNS drug discovery will follow, the relevant ones being those that use serotonin (5-HT), dopamine (DA), glutamate, gamma-aminobutyric acid (GABA), and acetylcholine (ACh). An overview of some specific examples where the fly is currently being used to investigate CNS function and to develop therapeutics will then be followed by a brief section on resources available when using Drosophila as a model system. At the conclusion of this review, it is hoped that the reader will have a basic grasp of key concepts in fly neurobiology and neuropharmacology, as well as the resources available to begin utilizing this model system for CNS drug discovery. In a practical sense, it is hoped that this review may encourage consideration of the use of D. melanogaster in laboratories that until now have not really had an appreciation of its unique advantages and power.
Section snippets
Serotonin
The serotonin (5-hydroxytryptamine; 5-HT) producing neurons of the adult fly have been mapped using antibodies against 5-HT. Serotonergic neurons arborize extensively through large neuropil regions in both the brain and optic ganglia (Valles & White, 1988). Studies of the functions of 5-HT systems in the fly have primarily focused upon the role of 5-HT in embryonic development (Saudou et al., 1992, Colas et al., 1999a, Colas et al., 1999b). Only recently has postsynaptic 5-HT receptor circuitry
Human neurological disorders modeled in Drosophila: neurodegeneration
One of the most promising fields of Drosophila research lies in increased understanding of basic mechanisms of human CNS disorders. Because of the level of conservation of basic cellular processes and neural function between human and fly, the study of neurodegenerative mechanisms in Drosophila will likely lead to a greater understanding of human neurodegenerative diseases. Importantly, studies in the fly offer the advantages of sophisticated genetics, rapid generation time, and ease of use
Neuropharmacology of drug abuse in Drosophila
A surprisingly informative field of research in Drosophila that has had important ramifications for the understanding of basic cognitive processes and higher order behaviors in both fly and human has been in the field of drug abuse. These studies have led to some very significant breakthroughs in understanding of learning and memory, circadian behaviors, and monoaminergic function. The study of how drugs of abuse alter Drosophila behaviors ultimately is a powerful platform for discovery of
Information
For investigators new to the fly, there are a number of very useful Internet-based sources of information and recent review articles (Bier, 2005, Matthews et al., 2005). The most comprehensive of the internet sites is Flybase (http://www.flybase.org), and this site should be the first you visit. Flybase is a database of the Drosophila genome, and contains cross-referenced data regarding all known and annotated fly genes, phenotypes of mutants, references, and reagents. There also are links to
Genetics
One of the most attractive aspects of Drosophila as a model system, and perhaps the most relevant to the drug discovery process, is the ability to perform high throughput modifier screens. In this process large scale random mutagenesis is performed, many thousands of flies are screened for a modification of the desired phenotype, and the mutant gene is subsequently identified using molecular biology techniques. This strategy was used to identify amnesiac as a component of the ethanol response,
Summary
The advantages and power of Drosophila (or other genetic models such as C. elegans) for lead compound generation and target identification include not only increased rate of discovery and reduced costs, but being able to follow a systems-based approach. It is widely recognized today that cell-based assays to develop novel therapies for CNS disorders do not serve as good models for complex and dynamic brain physiology. Even the simplest common mammalian system, the mouse, pales by comparison to
Acknowledgments
I would like to thank Dr. Val Watts and Dr. Don Ready for thoughtful discussions and critical reading of this manuscript, and Dr. John A Pollock for helpful comments.
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