Depression-like behavior of aged male and female mice is ameliorated with administration of testosterone or its metabolites

There may be a role of age-related decline in androgen production and/or its metabolism for late-onset depression disorders of men and women. Thus, the anti-depressant-like effects of testosterone (T) and its metabolites are of interest. Given that these androgens have disparate mechanisms of action, it is important to begin to characterize and compare their effects in an aged animal model. We hypothesized that there would be sex differences in depression behavior of aged mice and that androgens would reduce depression-like behaviors in the forced swim test. To investigate this, male and female mice (~ 24 months old) were subcutaneously administered T, or one of its 5α-reduced metabolites (dihydrotesterone-DHT, 5α-androstane,17β-diol-3α-diol), or aromatized metabolite (estradiol — E2), or oil vehicle. Mice were administered androgens (1 mg/kg) 1 h before being tested in the forced swim test, an animal model of depression. We found that males spent more time immobile, and less time swimming, than females. Administration of T, DHT, or 3α-diol similarly reduced time spent immobile, and increased time spent struggling, of male and female mice. E2, compared to vehicle administration, decreased time spent immobile of males and females, but increased time spent swimming of females and time spent struggling of male mice. Together, these data suggest that T and its 5α-reduced and aromatized metabolites have anti-depressant-like effects in aged male and female mice.