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. 2010 Apr 8:2:15.
doi: 10.3389/fnagi.2010.00015. eCollection 2010.

3alpha-androstanediol, but not testosterone, attenuates age-related decrements in cognitive, anxiety, and depressive behavior of male rats

Cheryl A Frye  1 , Kassandra L Edinger, Edwin D Lephart, Alicia A Walf
Affiliations

3alpha-androstanediol, but not testosterone, attenuates age-related decrements in cognitive, anxiety, and depressive behavior of male rats

Cheryl A Frye et al. Front Aging Neurosci. .

Abstract

Some hippocampally-influenced affective and/or cognitive processes decline with aging. The role of androgens in this process is of interest. Testosterone (T) is aromatized to estrogen, and reduced to dihydrotestosterone (DHT), which is converted to 5alpha-androstane, 3alpha, 17alpha-diol (3alpha-diol). To determine the extent to which some age-related decline in hippocampally-influenced behaviors may be due to androgens, we examined the effects of variation in androgen levels due to age, gonadectomy, and androgen replacement on cognitive (inhibitory avoidance, Morris water maze) and affective (defensive freezing, forced swim) behavior among young (4 months), middle-aged (13 months), and aged (24 months) male rats. Plasma and hippocampal levels of androgens were determined. In experiment 1, comparisons were made between 4-, 13-, and 24-month-old rats that were intact or gonadectomized (GDX) and administered a T-filled or empty silastic capsule. There was age-related decline in performance of the inhibitory avoidance, water maze, defensive freezing, and forced swim tasks, and hippocampal 3alpha-diol levels. Chronic, long-term (1-4 weeks) T-replacement reversed the effects of GDX in 4- and 13-month-old, but not 24-month-old, rats in the inhibitory avoidance task. Experiments 2 and 3 assessed whether acute subcutaneous T or 3alpha-diol, respectively, could reverse age-associated decline in performance. 3alpha-diol, but not T, compared to vehicle, improved performance in the inhibitory avoidance, water maze, forced swim, and defensive freezing tasks, irrespective of age. Thus, age is associated with a decrease in 3alpha-diol production and 3alpha-diol administration reinstates cognitive and affective performance of aged male rats.

Keywords: 3α-diol; affect; aging; androgens; cognition; depression; testosterone.

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Figures

Figure 1
Figure 1
Represents behavior of 4- (black bars), 13- (dark grey bars), and 24- (light grey bars) month-old rats that were left intact (solid bars), GDX (white bars), or GDX and T-replaced (striped bars) in the inhibitory avoidance task (A), water maze (B), defensive freezing task (C), and forced swim task (D). * over individual bars denotes significant difference (p < 0.05) of GDX rats compared to intact and T-replaced rats (p < 0.05). # above individual bars indicates a tendency to be different from intact rats (p < 0.075).* over brackets denotes difference at that age group compared to age groups that do not have a bracket above bars (p < 0.05).
Figure 2
Figure 2
Represents hippocampal levels of T (A), E2 (B), DHT (C), and 3α-diol (D) in of 4- (black bars), 13- (dark grey bars), and 24- (light grey bars) month-old rats that were left intact (solid bars), GDX (white bars), or GDX and T-replaced (striped bars). * over individual bars denotes significant difference (p < 0.05) of GDX rats compared to intact rats (p < 0.05). * over brackets denotes difference at that age group compared to age groups that do not have a bracket above bars (p < 0.05).
Figure 3
Figure 3
Represents behavior of 4- (black bars), 13- (dark grey bars), and 24- (light grey bars) month-old intact rats administered subcutaneous injections of sesame oil vehicle (solid bars) or T (stippled bars) in the inhibitory avoidance task (A), water maze (B), defensive freezing task (C), and forced swim task (D). * over brackets denotes difference at that age group compared to age groups that do not have a bracket above bars (p < 0.05).
Figure 4
Figure 4
Represents hippocampal levels of T (A), E2 (B), DHT (C), and 3α-diol (D) in – (black bars), 13- (dark grey bars), and 24- (light grey bars) month-old intact rats administered subcutaneous injections of sesame oil vehicle (solid bars) or T (stippled bars). * Over individual bars denotes significant difference (p < 0.05) of T-administration over vehicle (p < 0.05). * Over brackets denotes difference at that age group compared to age groups that do not have bracket above bars (p < 0.05).
Figure 5
Figure 5
Represents behavior of 4- (black bars), 13- (dark grey bars), and 24-(light grey bars) month-old intact rats administered subcutaneous injections of sesame oil vehicle (solid bars) or 3α-diol (checkered bars) in the inhibitory avoidance task (A), water maze (B), defensive freezing task (C), and forced swim task (D). *Denotes significant difference of 3α-diol administration compared to vehicle (p < 0.05). #Denotes tendency for differences of 13-month-old rats to 24-month-old rats (p < 0.075). * Over brackets denotes difference at that age group compared to age groups that do not have bracket above bars (p < 0.05).
Figure 6
Figure 6
Represents hippocampal levels of T (A), DHT (B), and 3α-diol (C) of 4- (black bars), 13- (dark grey bars), and 24- (light grey bars) month-old gonadally-intact rats administered subcutaneous injections of sesame oil vehicle (solid bars) or 3α-diol (checkered bars). *Denotes significant difference of 3α-diol administration compared to vehicle (p < 0.05). #Denotes tendency for differences of 13-month-old rats to 24-month-old rats (p < 0.075). * Over brackets denotes difference at that age group compared to age groups that do not have bracket above bars (p < 0.05).
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