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Graphical abstract Figure. No Caption available. HighlightsPramipexole (PPX) for 7 days prevented LPS‐induced depressant‐like behavior in mice.PPX prevented the LPS‐induced increase in IL‐1&bgr; in the hippocampus.PPX abolished the LPS‐induced increase in hippocampal protein 3‐nitrotyrosine.D2 receptor antagonist sulpiride did not prevent antidepressant‐like effect of PPX.Anti‐inflammatory properties of PPX may be eliciting antidepressant‐like effect. ABSTRACT Pramipexole (PPX), a dopamine D2/3 receptor preferring agonist, is currently in use for the treatment of Parkinson’s disease symptoms and restless legs syndrome. Recently, anti‐inflammatory properties of PPX have been shown in an autoimmune model of multiple sclerosis, and case reports indicate PPX ameliorates depressive symptoms. Since peripheral inflammation is known to induce depression‐like behavior in rodents, we assessed the potential antidepressant effect of PPX in an inflammatory model of depression induced by LPS. Repeated (daily for 7 days, 1 mg/kg, i.p.), but not acute (1 h before LPS) treatment with PPX abolished the depression‐like behavior induced by LPS (0.1 mg/kg, i.p.) in the forced swim test, and the anhedonic behavior in the splash test. Interestingly, PPX per se decreased interleukin 1&bgr; levels and reversed LPS‐induced increase in its content in mice hippocampus· Repeated PPX treatment also prevented the increase in hippocampal levels of the 3‐nitrotyrosine protein adducts induced by LPS. Haloperidol (0.2 mg/kg, i.p.) and sulpiride (50 mg/kg, i.p.) were unable to prevent the antidepressant‐like effect of PPX in LPS‐treated mice. Altogether, these results suggest that the observed antidepressant‐like effect of PPX in LPS‐treated mice may be dependent on its anti‐inflammatory properties and may not be related to dopamine D2 receptor activation.