Antidepressant-like properties of sarizotan in experimental Parkinsonism

RATIONALE: Depression and anxiety are common symptoms in Parkinson's disease for which there are no optimal treatments. Sarizotan, an agonist at serotonin receptors and partial agonist at dopamine D(2)-like receptors, has shown antidyskinetic effects in Parkinson's disease. Based on its pharmacological profile, we hypothesized that sarizotan could also have antidepressant-like properties. OBJECTIVES: Examine effects of sarizotan on behavioral and histological measures known to be regulated by established antidepressants in normal and unilaterally 6-hydroxydopamine-lesioned rats. RESULTS: Sarizotan was found to significantly reduce immobility in the modified forced swim test, a measure of antidepressant-like activity, but had no effects on thigmotaxis or corner time, measures of anxiety-like behavior, in the unilaterally 6-hydroxydopamine-lesioned rats. At the same dose, sarizotan counteracted l-DOPA/benserazide-induced supersentitized rotational behavior and dyskinesias without significantly affecting l-DOPA/benserazide-induced locomotion. At the histological level, sarizotan alone or in combination with l-DOPA/benserazide stimulated cell proliferation, measured by bromodeoxyuridine incorporation or Ki-67 staining, both in the subgranular zone of the dentate gyrus and in the subventricular zone of the striatum in the 6-hydroxydopamine-lesioned hemisphere. Likewise, combined sarizotan and l-DOPA/benserazide treatment stimulated doublecortin levels in the subgranular zone of the dentate gyrus. CONCLUSIONS: These significant effects of sarizotan in the modified forced swim test and on cell proliferation are reminiscent of those found after various antidepressant therapies. These data suggest that sarizotan may have some antidepressant-like and restorative properties in Parkinsonism.