Frye Cheryl A, Edinger Kassandra, Sumida Kanako
Department of Psychology, The University at Albany-SUNY, Albany, NY 12222, USA.
Neuropsychopharmacology. 2008 Apr;33(5):1049-61. doi: 10.1038/sj.npp.1301498. Epub 2007 Jul 11.
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.
尽管雄激素分泌会随着衰老而减少，这可能是认知和情感功能下降的原因，但雄激素介导这些行为的作用和机制尚未完全明确。睾酮（T）是主要的雄性激素，可芳香化为雌激素（E₂），并还原为二氢睾酮（DHT），后者再转化为5α-雄烷，3α，17β-二醇（3α-二醇）。为了确定T的神经活性代谢产物3α-二醇的作用是否介导认知和情感行为，分别给24月龄的老龄完整雄性C57/B6小鼠以及12周龄的年轻完整和去势（GDX）小鼠皮下注射T、3α-二醇、E₂或芝麻油载体（1mg/kg；每组n = 4 - 5只），每周一次，1小时后在活动箱、转棒、旷场、高架十字迷宫、零迷宫、镜像迷宫、明暗转换、强迫游泳或Vogel任务中对小鼠进行测试。对小鼠进行抑制性回避或条件性情境恐惧训练，训练后给予激素，然后进行测试。在最后一次测试后，收集组织以评估激素水平以及对γ-氨基丁酸（GABA）刺激的氯离子通量的影响。T、3α-二醇或E₂可增强老龄完整小鼠在旷场、明暗转换、镜像迷宫和强迫游泳任务中的抗焦虑和抗抑郁行为。T或3α-二醇，但不是E₂，可增强高架十字迷宫、零迷宫和Vogel任务中的抗焦虑行为，并增加活动监测器中的运动行为、转棒任务中的跌落潜伏期以及海马介导而非杏仁核介导的条件性恐惧任务和抑制性回避任务中的认知表现。抗焦虑和增强的认知表现与血浆和海马3α-二醇水平以及GABA刺激的氯离子通量增加的给药方案相关。在年轻成年去势小鼠中也观察到类似模式，但完整小鼠中未观察到。因此，3α-二醇可增强雄性小鼠的情感和认知行为。
