Bosentan, a mixed endothelin receptor antagonist, induces antidepressant-like activity in mice

•Bosentan reduces immobility time in the forced swimming test and tail suspension test.•Bosentan increases circulating IL-6 levels in mice exposed to forced swimming test.•This is the first evidence that endothelin mediates depression-like behavior.

Endothelins are peptides described initially as potent vasoactive mediators. Recently, studies reported that endothelins can modulate the production and release of cytokines by immune cells. In turn, cytokines are involved in depression disorders and also in the effectiveness of some antidepressants. Therefore, we investigated the effects of treating mice with bosentan, a mixed endothelin receptor antagonist, in widely used models for assessing antidepressant activity of compounds, the forced swimming (FST) and the tail suspension tests (TST). Moreover, the influence of bosentan treatment on circulating IL-6 levels was also addressed after FST. The results show that bosentan treatment induced a bell shaped dose-dependent antidepressant-like effect with increase in circulating IL-6 levels in animals exposed to FST. Bosentan also presented antidepressant-like effect in TST. Similar results were obtained with nortriptyline treatment in the FST and TST. Possible anxiogenic effect of bosentan was excluded using the elevated plus maze test. Therefore, this is the first study to demonstrate the antidepressant-like activity of bosentan in mice, unveiling a previous unrecognized role of endothelin in depression and its possible relation with increased circulating IL-6 levels.