Androgen administration to aged male mice increases anti-anxiety behavior and enhances cognitive performance

Abstract

Although androgen secretion is reduced with aging, and may underlie decrements in cognitive and affective performance, the effects and mechanisms of androgens to mediate these behaviors are not well understood. Testosterone (T), the primary male androgen, is aromatized to estrogen (E(2)), and reduced to dihydrotestosterone (DHT), which is converted to 5alpha-androstane, 3alpha, 17beta-diol (3alpha-diol). To ascertain whether actions of the neuroactive metabolite of T, 3alpha-diol, mediates cognitive and affective behaviors, intact, aged male C57/B6 mice (24 month old) as well as young, intact and gonadectomized (GDX; 12 week old) mice were administered s.c. T, 3alpha-diol, E(2), or sesame oil vehicle (1 mg/kg; n=4-5/group) at weekly intervals and 1 h later mice were tested in the activity box, roto-rod, open field, elevated plus maze, zero maze, mirror maze, dark-light transition, forced swim, or Vogel tasks. Mice were trained in the inhibitory avoidance or conditioned contextual fear and were administered hormones following training and then were tested. After the last test occasion, tissues were collected for evaluation of hormone levels and effects on gamma-aminobutyric acid (GABA)-stimulated chloride flux. T, 3alpha-diol, or E(2) increased anti-anxiety and antidepressant behavior of aged, intact mice in the open field, light-dark transition, mirror maze, and forced swim tasks. T or 3alpha-diol, but not E(2), enhanced anti-anxiety behavior in the elevated plus maze, zero maze, and the Vogel task, and increased motor behavior in the activity monitor, latency to fall in the Roto-rod task, and cognitive performance in the hippocampally-mediated, but not the amygdala-mediated, portion of the conditioned fear task and in the inhibitory avoidance task. Anti-anxiety and enhanced cognitive performance was associated with regimen that increased plasma and hippocampal 3alpha-diol levels and GABA-stimulated chloride flux. Similar patterns were seen among young, adult GDX but not in intact mice. Thus, 3alpha-diol can enhance affective and cognitive behavior of male mice.

Figure 1

Represents mean affective behavior for aged, intact male mice administered vehicle control (white bar), E₂ (horizontally-striped bar), T (black bar), or 3α-diol (gray bar) in the open field (upper left panel), elevated plus maze (upper right panel), dark—light transition (middle left panel), zero maze (middle right panel), mirror maze (lower left panel), and forced swim (lower nght panel) taste. *Significant difference (P<0.05).

Figure 2

Represents mean affective behavior for young, intact male mice administered vehicle control (white bar), E₂ (horizontally-striped bar), T (black bar), or 3α-diol (gray bar) in the open field (upper left panel), elevated plus maze (upper right panel), dark–light transrtion (middle left panel), zero maze (middle right panel), mirror maze (lower left panel), and forced swim (lower right panel) tasks, *Significant difference (P<0.05), ^#denotes significant trend (P<0.10).

Figure 3

Represents mean affective behavior for young, gonadectomized (GDX) mice administered vehicle control (white bar), E₂ (horizontally-striped bar), T (black bar), or 3α-diol (gray bar) in the open field (upper left panel), elevated plus maze (upper right panel), dark–light transition (middle left panel), zero maze (middle right panel), mirror maze (lower left panel), and forced swim (lower right panel) tasks. *Denotes significant difference (P<0.05), ^#denotes significant trend (P<0.10).

Figure 4

Represents mean cognitive behavior for aged, intact male mice administered vehicle control (white bar). E₂ (horizontally-striped bar), T (black bar), or 3α-diol (gray bar) in the inhibitory avoidance task (top panel), the hippocampally-mediated portion of the conditioned contextual fear task (middle panel), and the amygdala-mediated portion of the conditioned contextual fear task (lower panel). *Denotes significant difference (P<0.05). ^#denotes significant trend (P<0.10).

Figure 5

Represents mean cognitive behavior for young, intact male mice administered vehicle control (white bar), E₂ (horizontally-striped bar). T (black bar), or 3α-diol (gray bar) in the inhibitory avoidance task (top panel), the hippocampally-mediated portion of the conditioned contextual fear task (middle panel), and the amygdala-mediated portion of the conditioned contextual fear task (lower panel). *Denotes significant difference (P<0.05).

Figure 6

Represents mean cognitive behavior for young, gonadectomized (GDX) male mice administered vehicle control (white bar), E₂ (horizontally-striped bar), T (black bar), or 3α-diol (gray bar) in the inhibitory avoidance task (top panel), the hippocampally-mediated portion of the conditioned contextual fear task (middle panel), and the amygdala-mediated portion of the conditioned contextual fear task (lower panel), ^#denotes significant trend (P<0.10).