Bethea C L, Coleman K, Phu K, Reddy A P, Phu A
Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, OR 97006, United States; Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, United States; Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97201, United States.
Behavioral Sciences Unit, Division of Comparative Medicine, Oregon National Primate Research Center, Beaverton, OR 97006, United States.
Neuroscience. 2014 Aug 22;274:341-56. doi: 10.1016/j.neuroscience.2014.05.056. Epub 2014 Jun 5.
Androgen administration to castrated individuals was purported to decrease activity in the serotonin system. However, we found that androgen administration to castrated male macaques increased fenfluramine-induced serotonin release as reflected by increased prolactin secretion. In this study, we sought to define the effects of androgens and aromatase inhibition on serotonin-related gene expression in the dorsal raphe, as well as serotonergic innervation of the LC. Male Japanese macaques (Macaca fuscata) were castrated for 5-7 months and then treated for 3 months with (1) placebo, (2) testosterone (T), (3) dihydrotestosterone (DHT; non-aromatizable androgen) and ATD (steroidal aromatase inhibitor), or (4) Flutamide (FLUT; androgen antagonist) and ATD (n=5/group). This study reports the expression of serotonin-related genes: tryptophan hydroxylase 2 (TPH2), serotonin reuptake transporter (SERT) and the serotonin 1A autoreceptor (5HT1A) using digoxigenin-ISH and image analysis. To examine the production of serotonin and the serotonergic innervation of a target area underlying arousal and vigilance, we measured the serotonin axon density entering the LC with ICC and image analysis. TPH2 and SERT expression were significantly elevated in T- and DHT + ATD-treated groups over placebo- and FLUT + ATD-treated groups in the dorsal raphe (p < 0.007). There was no difference in 5HT1A expression between the groups. There was a significant decrease in the pixel area of serotonin axons and in the number of varicosities in the LC across the treatment groups with T > placebo > DHT + ATD = FLUT + ATD treatments. Comparatively, T- and DHT + ATD-treated groups had elevated TPH2 and SERT gene expression, but the DHT + ATD group had markedly suppressed serotonin axon density relative to the T-treated group. Further comparison with previously published data indicated that TPH2 and SERT expression reflected yawning and basal prolactin secretion. The serotonin axon density in the LC agreed with the area under the fenfluramine-stimulated prolactin curve, providing a morphological basis for the pharmacological results. This suggested that androgen activity increased TPH2 and SERT gene expression but, aromatase activity, and neural production of estradiol (E), may subserve axonal serotonin and determination of the compartment acted upon by fenfluramine. In summary, androgens stimulated serotonin-related gene expression, but aromatase inhibition dissociated gene expression from the serotonin innervation of the LC terminal field and fenfluramine-stimulated prolactin secretion.
给去势个体施用雄激素据称会降低血清素系统的活性。然而，我们发现给去势的雄性猕猴施用雄激素会增加芬氟拉明诱导的血清素释放，这可通过催乳素分泌增加来反映。在本研究中，我们试图确定雄激素和芳香化酶抑制对中缝背核中血清素相关基因表达以及蓝斑的5-羟色胺能神经支配的影响。雄性日本猕猴（食蟹猴）去势5至7个月，然后用以下方法治疗3个月：(1)安慰剂，(2)睾酮（T），(3)二氢睾酮（DHT；不可芳香化的雄激素）和阿那曲唑（ATD；甾体芳香化酶抑制剂），或(4)氟他胺（FLUT；雄激素拮抗剂）和阿那曲唑（每组n = 5）。本研究使用地高辛原位杂交和图像分析报告了血清素相关基因：色氨酸羟化酶2（TPH2）、血清素再摄取转运体（SERT）和血清素1A自身受体（5HT1A）的表达。为了检查血清素的产生以及觉醒和警觉背后目标区域的5-羟色胺能神经支配，我们用免疫细胞化学和图像分析测量了进入蓝斑的血清素轴突密度。在中缝背核中，T组和DHT + ATD处理组的TPH2和SERT表达显著高于安慰剂组和FLUT + ATD处理组（p < 0.007）。各组之间5HT1A表达无差异。在各治疗组中，血清素轴突的像素面积和蓝斑中膨体数量均有显著下降，处理顺序为T > 安慰剂 > DHT + ATD = FLUT + ATD。相比之下，T组和DHT + ATD处理组的TPH2和SERT基因表达升高，但DHT + ATD组相对于T处理组的血清素轴突密度明显受到抑制。与先前发表的数据进一步比较表明，TPH2和SERT表达反映了打哈欠和基础催乳素分泌。蓝斑中的血清素轴突密度与芬氟拉明刺激的催乳素曲线下面积一致，为药理学结果提供了形态学基础。这表明雄激素活性增加了TPH2和SERT基因表达，但芳香化酶活性以及雌二醇（E）的神经产生可能有助于轴突血清素的产生以及确定芬氟拉明作用的区域。总之，雄激素刺激了血清素相关基因表达，但芳香化酶抑制使基因表达与蓝斑终末场的血清素神经支配以及芬氟拉明刺激的催乳素分泌脱节。
