A behavioral analysis, validation, and mechanistic analysis of the effects of selective serotonin reuptake inhibitors in the rat forced swimming test model of human major depression

The forced swimming test (FST) is a behavioral screen for antidepressant drugs. It consists of placing rats in a jar of water from which they cannot escape for a 15-min forced swim, followed 24 hr later by a similar 5-min swim. Drugs which are effective antidepressants increase the activity of rats in the second swim. One major drawback of the FST is that selective serotonin reuptake inhibitors (SSRIs) such as Prozac, which are effective in treating human depression, have not been shown to increase activity in the FST. In Experiment 1, SSRIs and selective norepinephrine reuptake inhibitors (SNRIs) were tested, and several distinct forms of activity were observed, including swimming, climbing and diving. The results were that the SNRIs increased climbing, whereas the SSRIs increased swimming. These results showed that the SSRIs are active in the FST and produce a distinct behavioral outcome. A second drawback is that antidepressant drugs produce behavioral changes within 24 hours in the FST, in contrast to the recovery from clinical depression in humans, which usually takes weeks of treatment. In Experiment 2, brief and long-term treatment with an SSRI and SNRI were tested, at doses comparable to those used in humans. The results demonstrated that SSRIs and SNRIs increased activity at these doses, but only after long-term administration. These results strengthen the validity of the FST as an animal model of human depression. In Experiment 3, various selective serotonin (5-HT) receptor agonists and antagonists were studied to determine the receptor mechanism of the effect of SSRIs in the FST. The effects of an SSRI were prevented by pretreatment with p-chlorophenylalanine, a serotonin synthesis inhibitor. The SSRI\u27s effects were also blocked by 5-HT$\rm\sb{1A/1B}$ receptor antagonists and mimicked by 5-HT$\rm\sb{1A}$ and 5-HT$\rm\sb{1B}$ receptor agonists. These results demonstrate that the 5-HT$\rm\sb{1A}$ and 5-HT$\rm\sb{1B}$ receptors may mediate serotonergic antidepressant-like effects