Trends in Pharmacological Sciences
ReviewAssessing antidepressant activity in rodents: recent developments and future needs
Section snippets
The forced swim test
The forced swim test (FST) was developed by Porsolt and colleagues [6] in the rat and, subsequently, in the mouse [7]. This test is the most widely used tool for assessing antidepressant activity preclinically. The widespread use of this model is largely a result of its ease of use, reliability across laboratories and ability to detect a broad spectrum of antidepressant agents [8]. The test is based on the observation that rats, following initial escape-oriented movements, develop an immobile
Models based on drug-withdrawal-induced anhedonia
Reward deficits associated with withdrawal from drugs of abuse can represent an animal model of the symptom of ‘diminished interest or pleasure (anhedonia)’ with construct, convergent and predictive validities 4., 33.. Recent studies showed that amphetamine withdrawal is characterized by decreased breaking-points under a progressive ratio schedule for a sucrose solution reinforcer [34]. Under the progressive ratio schedule animals are required to increase their operant responding for a fixed
Strain differences in animal models of depression
The burgeoning use of genetically altered mice in behavioral pharmacology has resulted in much emphasis being placed on studying individual strain differences in both baseline behavior and in the response to psychotropic medications in mice [42]. In almost all of the behavioral models outlined above, substantial strain differences have been observed. Further analyses of both inbred and outbred strains might help reveal phenotypic behavioral differences that might have an underlying genetic
Species differences – new targets
It is becoming apparent that there are distinct species differences in the primary targets of certain psychotropic agents, which makes translation or prediction of effects from rat or mouse to human difficult. Tachykinin NK1 and 5-HT1B receptors are but two examples of receptors relevant to antidepressant action whereby important structural differences between the human and the rat and/or mouse interfere with the ability to predict pharmacological effects across species 52., 53.. Although
Future directions
Traditionally, the use of animal models has been instrumental in detecting antidepressant compounds based on a known pharmacology. Models such as the FST, olfactory bulbectomy and learned helplessness, which were validated originally for detection of tricyclic antidepressants and monoamine oxidase inhibitors, should detect related compounds with ease. It remains unclear as to whether currently used paradigms can systematically detect antidepressant agents with non-monoamine mechanisms of
Concluding remarks
It is clear from our experience that current models need to be refined continuously or new models developed to reveal the therapeutic potential of a broad range of compounds, as was the case with the introduction of SSRIs. Indeed, battery-style testing of various paradigms modeled on different endophenotypes of the depression syndrome, be it anhedonia or stress-induced coping, is encouraged.
The refinement of animal models over past years has demonstrated that many traditional paradigms are
Acknowledgements
A.M. was supported by a Novartis Pharma AG Research grant and I.L. was supported by grants USPHS R01 MH36262 and P05 MH48125 from the National Institute of Mental Health. We would like to thank Paul J. Kenny and Alasdair M. Barr for their helpful comments on the manuscript. We would also like to thank Peggy Myer from the Dept of Biomedical Graphics of The Scripps Research Institute for her assistance with graphics, and Mike Arends for editorial assistance. This is publication 14527-NP from The
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