Review
Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test

https://doi.org/10.1016/j.neubiorev.2005.03.008Get rights and content

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressant class today and exert their antidepressant-like effects by increasing synaptic concentrations of serotonin (5-HT). The rat forced swim test (FST) is the most widely used animal test predictive of antidepressant action. Procedural modifications recently introduced by our laboratory have enabled SSRI-induced behavioral responses to be measured in the modified FST. The use of this model to understand the pharmacological and physiological mechanisms underlying the role of 5-HT in the behavioral effects of antidepressant drugs is reviewed. Although all antidepressants reduced behavioral immobility, those antidepressants that increase serotonergic neurotransmission predominantly increase swimming behavior whereas those that increase catacholaminergic neurotransmission increase climbing behavior. The 5-HT1A, 5-HT1B/1D and 5-HT2C receptors are the 5-HT receptors most important to the therapeutic effects of SSRIs, based on extensive evaluation of agonists and antagonists of individual 5-HT receptor subtypes. Studies involving chronic administration have shown that the effects of antidepressants are augmented following chronic treatment. Other studies have demonstrated strain differences in the response to serotonergic compounds. Finally, a physiological model of performance in the rat FST has been proposed involving the regulation of 5-HT transmission by corticotropin releasing factor (CRF).

Introduction

Animal models predictive of antidepressant action have been used extensively in the development of novel therapeutic compounds and for understanding the neural substrates underlying depressive behavior (McKinney and Bunney, 1969, Weiss and Kilts, 1998, Willner and Mitchell, 2002, Geyer and Markou, 2002, Cryan et al., 2002a, Holmes, 2003). The forced swim test (FST), described originally by Porsolt et al., 1977, Porsolt et al., 1978, is the most widely used model for assessing pharmacological antidepressant activity. The test is based upon the observation that rodents eventually develop immobility when they are placed in cylinder of water after they stop active escape behaviors, such as climbing or swimming. Antidepressant treatments reduce the amount of immobility, or delay its onset, and increase or prolong active escape behaviors displayed during the FST. Despite acknowledged success at measuring the acute effects of a variety of antidepressant treatments, the use of the FST in depression research is fraught with controversy. Competing accounts for what the behavior in the FST means have sometimes made it difficult to understand whether treatment effects with antidepressants facilitate coping with stress or are due to behavioral impairment. While used as a principle screen for studying the neuropharmacology of reference drugs and discovering new antidepressants, the ability of the FST to detect novel types of antidepressants is frequently questioned. Does sensitivity to acute pharmacological effects preclude investigation of chronic treatment effects?

What makes the FST a special test is its ability to measure behavioral effects common to antidepressant treatments that have diverse pharmacological and physiological effects. Few behavioral tests exist with similar capability. Our laboratory made a number of procedural modifications to the rat FST about 10 years ago that improved the ability of the test to measure the effects of antidepressants (Detke et al., 1995, Lucki, 1997). The procedural modifications were prompted by the need to measure the behavioral effects of selective serotonin reuptake inhibitors (SSRIs), the most popularly prescribed class of antidepressant drugs, and to determine the role of serotonin (5-HT) receptors in these behavioral effects. This review summarizes some of the contributions that the modified rat FST has made towards understanding the validity of the FST, for establishing prescribed observation procedures to improve the detection of new drugs from different laboratories, for evaluating the role of different 5-HT receptors in the behavioral actions of antidepressants and for understanding the neural substrates underlying behavioral performance in the FST.

Section snippets

Predictive validity

The sensitivity of the rat FST to an impressively broad range of antidepressant drugs is one of the most important features supporting its primary use as a screen in antidepressant discovery research. Clinically effective treatments for depression that are detected by the rat FST include: tricyclics, monoamine oxidase inhibitors, atypical antidepressants, and somatic treatments, such as electroconvulsive shock, rapid eye movement sleep deprivation, exercise and transcranial magnetic stimulation

The modified rat forced swimming test

The FST originally developed by Porsolt et al., 1977, Porsolt et al., 1978 for use with rats and mice has been used to measure the effects of antidepressant treatments from many classes, including tricyclic compounds, MAOIs, many atypical compounds, electroconvulsive shock, and sleep deprivation (Borsini and Meli, 1988). The convergent effects of these diverse treatments supported the use of this model to predict compounds with potential clinical antidepressant activity. However, in its

A review of serotonergic compounds in the modified rat FST

A benefit from the development of the modified rat FST has been the reliable detection of SSRIs. The FST model then enabled further efforts to define the mechanism of action of SSRIs. In the next section of the review, we will describe the results of FST studies using serotonergic compounds, many of which have come from our laboratory.

Behavioral plasticity induced by swim stress

Although it is clear that serotonergic ligands alter behavior in the modified FST the neural circuitry underlying these effects remain to be fully elucidated. Emerging data suggest that the stress-related neuropeptide, corticotropin-releasing factor (CRF), is one potential mediator of acute behavioral responses to swim stress and of behavioral plasticity associated with repeated swim (Price et al., 2002). A series of studies have constructed a physiological model where regulation of the effects

Conclusion

The modified rat FST has become accepted as an improved method for characterizing the effects of antidepressant drugs and also for studying the neural substrates underlying their behavioral effects. The extensive data collected with the modified rat FST suggests that serotonergic antidepressants induce a distinct behavioral profile in the FST compared to antidepressants that act through catecholamine mechanisms. Procedural aspects of the test have become more standardized across laboratories,

Acknowledgements

The authors would like to gratefully acknowledge the contributions of Drs Michael J. Detke, Carolina Lopez-Rubelcava, Michelle E. Page and Jean-Philippe Reneric in the generation of some of the data referred to in this review. This research was supported by United States Public Health Services grant MH 36262, MH 48125, and MH 58250 and by NAR SAD.

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    Present address: Neuroscience Research, Novartis Institutes of BioMedical Research, Novartis Pharma AG, Basel, Switzerland.

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