The Rodent Forced Swim Test Measures Stress-Coping Strategy, Not Depression-like Behavior

Abstract

The forced swim test (FST) measures coping strategy to an acute inescapable stress and thus provides unique insight into the neural limb of the stress response. Stress, particularly chronic stress, is a contributing factor to depression in humans and depression is associated with altered response to stress. In addition, drugs that are effective antidepressants in humans typically promote active coping strategy in the FST. As a consequence, passive coping in the FST has become loosely equated with depression and is often referred to as "depression-like" behavior. This terminology oversimplifies complex biology and misrepresents both the utility and limitations of the FST. The FST provides little construct- or face-validity to support an interpretation as "depression-like" behavior. While stress coping and the FST are arguably relevant to depression, there are likely many factors that can influence stress coping strategy. Importantly, there are other neuropsychiatric disorders characterized by altered responses to stress and difficulty in adapting to change. One of these is autism spectrum disorder (ASD), and several mouse genetic models of ASD exhibit altered stress-coping strategies in the FST. Here we review evidence that argues a more thoughtful consideration of the FST, and more precise terminology, would benefit the study of stress and disorders characterized by altered response to stress, which include but are not limited to depression.

Keywords: Porsolt; Stress; addiction; antidepressants; autism; behavior; serotonin.

Figure 1

(A) Current scheme: the forced swim test (FST) is interpreted in the context of depression/antidepressant action. However, the FST has poor construct and face validity as either a model or a test for depression, and not all of the factors that change coping strategy in the FST are relevant to depression. (B) Proposed scheme: The FST gives unique insight by measuring coping strategy to an acute, inescapable, ethologically relevant stress; but is not a model or a stand-alone test of any psychopathology. Rather, stress-coping strategy in the FST can be modified by factors relevant to depression and antidepressant efficacy, arousal state, metabolic state, as well as additional neuropsychiatric conditions including autism spectrum disorder (ASD) and substance use disorder. For stress coping, the FST has excellent construct validity. The observation that depression, ASD, and substance use disorder are all associated with altered response to stress lends face validity for use of the FST in each of these contexts.

Figure 2

“Facts are contained in the [data]. The fabric of speculation against which they are projected is thin indeed and has to be rewoven many times before it will stand much wear”. The mind-state of a rodent relevant to depression is the subject of speculation. Data from the forced swim test is an important thread of evidence that has to be carefully considered with respect to the entire behavioral and experimental context to support a compelling interpretation.