ReviewFactors influencing behavior in the forced swim test
Introduction
Major depressive disorder is a global medical problem due to its high prevalence and incomplete responsiveness to treatment [1]. Screening of novel antidepressants is an important practice in modern research due to the limited efficacy and large number of side effects of existing treatments [2]. The forced swim test (FST), also known as the ‘behavioral despair’ test, was developed in 1978 by Porsolt et al. [3] as a rodent model for predicting the clinical efficacy of antidepressant drugs.
The basic FST involves two sessions with animals placed in a cylinder containing 25 °C water, from which they cannot escape. The first session is a 15-min pretest that is followed 24 h later by a 5-min test session. The pretest is a stressor which is thought to induce a state of behavioral despair [4] or passive stress coping strategy [5], since the animals become more immobile as the test session progresses. The typical posture of immobility is characterized by floating in the water with only movements necessary to keep the nose above the surface. The immobility time and also the latency to the initial immobility period [6] are the primary dependent measures. A wide range of antidepressant drugs injected between the pretest and test periods decrease the duration of immobility in the test, i.e., makes the rats more active [7].
In 1996, Detke and coauthors added evaluation of active behavior during the FST — climbing: vertical movements against walls; swimming: horizontal movements across the water surface; and diving. This modified version facilitates differentiation between the major classes of antidepressant drugs in rats [8]. Treatment with norepinephrine-targeting antidepressants selectively increases climbing in the FST, while drugs influencing serotonin neurotransmission enhance swimming behavior. Adding measurement of the latency to immobility to the standard procedure increases the sensitivity of the FST in both mice and rats [6], [9].
The FST is also used for assessment of depressive-like behavior in animal models of psychiatric disorders [10], [11], [12]. The behavioral and biochemical characteristics of animals in a state of learned helplessness produced by a period of inescapable swimming during the FST have led some investigators to believe this condition itself provides a useful animal model of depression [13], [14]. Forced swim provokes neurochemical and endocrine alterations [15], [16] and is used as a stressor by itself [17], [18].
Despite the simplicity and sensitivity of the FST procedure, large differences even in baseline immobility rates have been reported between different working groups, which complicate the comparison of results across studies. To illustrate this, some examples of differences in immobility scored in control animals of the two most commonly used strains of rats, Sprague–Dawley and Wistar, are presented in Table 1.
In this review, we have analyzed the published literature included in the PubMed MEDLINE database for factors that may influence rodent behavior in the FST and attempt to describe those variables that should be considered in studies employing the FST. First, factors which are known to influence FST results were chosen (e.g. physical environmental factors such as light and noise; biological factors such as age, sex, and strain; and manipulations before test, such as housing and handling). As the FST was developed for the rat, and active behaviors estimated mostly for the rat, keywords for this search included “factor of interest + forced swim test + rat”. Sometimes, due to a low number of search results, (less than 10), keywords were changed to “factor of interest + forced swim test”, and results from other species, mostly mice, were included. If the search yielded more than 1000 results (as in the case of antidepressant treatment), only reviews were considered.
Section snippets
Strain of animals
Behavioral strategies in the FST can vary significantly with animal strain [53], [54], [55]. Even obtaining Wistar or Sprague–Dawley rats from different suppliers may yield different findings [4]. A significant decrease of struggling between first and second sessions of the FST was observed in spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) but not in Fisher 344 or Lewis (LEW) rats [55]. Strain differences also exist in antidepressant efficacy [28], [56], [57].
Certain specific rat
Handling
Short-term handling daily for 5 days prior to the FST did not affect immobility time in rats, but long-term handling (2 months daily before the FST) increased immobility time in the study [84] (Table 2).
Housing
Exposing laboratory animals to physical or social stimulation greater than they would receive under standard housing conditions either had no effect on immobility [36], [85] or had an antidepressant-like effect (Table 2).
Rats housed in an enriched environment exhibited less immobility [3] and more
Test equipment and settings
Tank dimensions play a significant role in determining behavior in the FST. In Porsolt's original version of the test, the tank was 40 cm in height and 18 cm in diameter; it was designed to have depth of 15 cm water, shallow enough for the rat to feel the bottom with its hind paws and tail [3]; animals developed a floating posture quickly and this resulted in more immobility during the second test session. The modified version of the FST involved increasing water depth to 30 cm, so the rat was
Conclusions
The FST, in its classical or modified version, provides a unique opportunity to assess antidepressant efficacy in a rapid, low-cost, and reliable manner. Its strong predictive and discriminative validity serves for reliable assessment of neurological mechanisms of antidepressant action. A large and growing number of studies also use the FST to assess depressive-like behavior in animal models of mood disorders.
To summarize, there are several suggestions which may help to improve quality of the
Acknowledgments
This research is supported by funds from the Utah Science Technology and Research (USTAR) initiative and the VISN19 MIRECC to Dr. Perry Renshaw.
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