Mouse Models for Drug Discovery Methods and Protocols
As the drug discovery process shifts more and more toward specifically targeting pathways and molecules, model systems continue to increase in importance, and the mouse, with its versatility, ease of use, and remarkable similarity to the human genome, has
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1. Introduction Animal models are widely used for simulating human brain disorders and for providing insight into their neurobiological mechanisms (1–4). The latter is of great interest in the current neuroscientific community, given the increasing use of laboratory animals for screening various classes of psychotropic drugs (5, 6). The use of mice has been particularly beneficial, since fine-tuned manipulations of selected genes have led to new animal models relevant to drug discovery (3, 4, 7, 8). G. Proetzel, M.V. Wiles (eds.), Mouse Models for Drug Discovery, Methods in Molecular Biology 602, DOI 10.1007/978-1-60761-058-8 18, © Humana Press, a part of Springer Science+Business Media, LLC 2010
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It is important to understand, however, that any animal experiment in the laboratory is an artificial situation, and it may be biologically different from the natural behavior of the animal. Thus, it is crucial to correctly interpret the animal behavior observed in an experiment in order to identify parallels with specific human brain disorders. Although there are many other conceptual and methodological limitations of working with mice, this species shows much promise for future psychopharmacological research. In order for animal models to be useful, researchers must follow certain practices and methods which will optimize the translatability of data from animal models to human affective disorders. Here, we will present a broad review of some reliable methods of analyzing mouse anxiety, and their utility for screening for anxiolytic therapeutic agents. All these tests are of a complex nature and we would suggest that the reader explore each system to better understand the variables and subtleties of each test. We will also discuss how these protocols can be applied correctly, in order to avoid confounding experimental data.
2. Materials 2.1. Animals
1. Various inbred, selectively bred (for specific behavioral/physiological phenotypes), and genetically modified (mutant or transgenic) mice may be used, and some searchable online databases, such as Mouse Phenome Project (www.jax.org/phenome) or Mouse Genome Informatics (www.informatics.jax.org/), may provide appropriate strains for studying mouse anxiety. We recommend using most of the inbred strains listed in the Tier 1 list of the Mouse Phenome Project database, especially C57BL/6J, A/J, and 129S1/SvImJ mice (see http://phenome.jax.org/pub-cgi/phenome/mpdcgi?rtn= docs/pristrains for details) (see Note 1). 2. Generally, several different models of anxiety that target different domains (e.g., locomotion/exploration, risk assessment, defensive responses) are necessary in order to more fully characterize drug effects or a mutant mouse phenotype. The use of a single model, or only models targeting one particular behavioral domain, may not be sufficient. 3. Researchers should also take other factors like age, weight, sex, stage of estrous cycle, diet, and housing situation into account when designing experiments (see Note 2).
Experimental Models of A
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