Sex and age differences in the antidepressant-like effect of fluoxetine in the forced swim test

•FLX reduces immobility in females of all ages but had no effect in senescent males.•Young females respond to lower doses of FLX than males.•In senescent males FLX lacks antidepressant effect but produces motor incoordination.

This study compared in males and females of three representative ages: young adults (3-5 months old), middle-aged (12-15 months old) and senescent (23-25 months old) the antidepressant-like effect of fluoxetine (FLX, 5.0 and 10 mg/kg) in the forced swim test (FST). Intact (non gonadectomized) rats were evaluated. Young adult females were chosen in proestrus/estrus or in metestrus/diestrus, while middle-aged and senescent females were selected in metestrus/diestrus. Locomotion and motor coordination were also recorded. Under basal conditions (without FLX), young adult and middle-aged females showed less immobility than males. This sex difference disappeared at senescence because males diminished their levels of immobility. Thus, senescent males showed lower immobility than middle-aged and young males. FLX (5 and 10 mg/kg) produced similar actions in young females irrespective of their estrous cycle phase, therefore, these subgroups were pooled in a single one. Young adult and middle aged females clearly responded to 5 and 10 mg/kg of FLX with a reduction in immobility, while young adult and middle-aged males only did to 10 mg/kg. In senescent females 10 mg/kg FLX reduced immobility. Remarkably, in senescent males this FLX dose did not produce an antidepressant-like effect. FLX marginally affected locomotion; however, at its highest dose (10 mg/kg), and only in senescent males, interfered with motor coordination tested in the rotarod. These data show that sex and aging influence behavioral despair without treatment and after FLX.