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.

Anger is an approach-related affect: Evidence and implications.

“…High testosterone is associated with feelings of vigor and activation (Dabbs, Strong, & Milun, 1997;Sherwin, 1988), and testosterone is an effective antidepressant in clinical populations with very low or absent endogenous testosterone production (e.g., Rabkin, Wagner, & Rabkin, 1996). Elevation in testosterone also reduces defensive (fear) responses in a number of species (e.g., Boissy & Bouissou, 1994;Frye, Edinger, & Sumida, 2008;Vandenheede & Bouissou, 1993). An attentional bias for fearful faces (which relates to elevations in fear and anxiety) diminishes after administration of testosterone; conversely, attentional bias for angry faces has been linked with both higher levels of approach motivation (e.g., BAS scores and anger) and higher testosterone (for review, see van Honk & Schutter, 2007).…”

Progesterone enhances performance of aged mice in cortical or hippocampal tasks

“…We have previously demonstrated that testosterone levels of intact aged male mice (plasma =∼0.4±0.1 hippocampus =∼0.3±0.1 ng/g) are similar to those observed in young, gdx mice (plasma =∼0.3±0.3 ng/ml, hippocampus =∼0.4±0.1 ng/g vs. young, intact male mice plasma =∼2.7±1.5 ng/ml, hippocampus =∼1.0±0.3 ng/g) [15]. Aged female mice have levels in the hippocampus of E 2 (∼2.0±1.0 ng/g) and the P 4 metabolite, 5α-pregnan 3α-ol-20-one (3α,5α-THP; ∼2.0±0.5 ng/g) that are more similar to young diestrous (E 2 ∼10.0±3.0 ng/g; 3α,5α-THP ∼0.7±0.5 ng/g) than to young proestrous mice (E 2 ∼40.5±8.1 ng/g; 3α,5α-THP ∼19.4±4.6 ng/g) [12,13].…”

“…There was a main effect of P 4 (F(1,9) = 15.10, P = 0.004), but not sex (F(1,9) = 2.03, P = 0.19), and no interaction (F(1,9) = 2.72, P = 0.13). Young control mice typically have latencies of 40-50 s to crossover to the dark, shock-associated side of the chamber in this task [11,15].…”

“…The primary measures for each task are described below [13][14][15][16]. Motor and/or sensory responses were recorded during testing and no differences were noted.…”

Progesterone to ovariectomized mice enhances cognitive performance in the spontaneous alternation, object recognition, but not placement, water maze, and contextual and cued conditioned fear tasks

“…Conditioned Fear was modified from previously described methods (Frye, Edinger, & Sumida, 2008). Mice were habituated to the conditioning chamber for 4 min.…”