Donner N, Handa R J
Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80526, USA.
Neuroscience. 2009 Oct 6;163(2):705-18. doi: 10.1016/j.neuroscience.2009.06.046. Epub 2009 Jun 23.
Dysfunctions of the brain 5-HT system are often associated with affective disorders, such as depression. The raphe nuclei target the limbic system and most forebrain areas and constitute the main source of 5-HT in the brain. All 5-HT neurons express tryptophan hydroxylase-2 (TPH2), the brain specific, rate-limiting enzyme for 5-HT synthesis. Estrogen receptor (ER) beta agonists have been shown to attenuate anxiety- and despair-like behaviors in rodent models. Therefore, we tested the hypothesis that ER beta may contribute to the regulation of gene expression in 5-HT neurons of the dorsal raphe nuclei (DRN) by examining the effects of systemic and local application of the selective ER beta agonist diarylpropionitrile (DPN) on tph2 mRNA expression. Ovariectomized (OVX) female rats were injected s.c. with DPN or vehicle once daily for 8 days. In situ hybridization revealed that systemic DPN-treatment elevated basal tph2 mRNA expression in the caudal and mid-dorsal DRN. Behavioral testing of all animals in the open field (OF) and on the elevated plus maze (EPM) on days 6 and 7 of treatment confirmed the anxiolytic nature of ER beta activation. Another cohort of female OVX rats was stereotaxically implanted bilaterally with hormone-containing wax pellets flanking the DRN. Pellets contained 17-beta-estradiol (E), DPN, or no hormone. Both DPN and E significantly enhanced tph2 mRNA expression in the mid-dorsal DRN. DPN also increased tph2 mRNA in the caudal DRN. DPN- and E-treated rats displayed a more active stress-coping behavior in the forced-swim test (FST). No behavioral differences were found in the OF or on the EPM. These data indicate that ER beta acts at the level of the rat DRN to modulate tph2 mRNA expression and thereby influence 5-HT synthesis in DRN subregions. Our results also suggest that local activation of ER beta neurons in the DRN may be sufficient to decrease despair-like behavior, but not anxiolytic behaviors.
大脑5-羟色胺（5-HT）系统功能障碍常与情感障碍如抑郁症相关。中缝核靶向边缘系统和大多数前脑区域，构成大脑中5-HT的主要来源。所有5-HT神经元均表达色氨酸羟化酶-2（TPH2），这是大脑中5-HT合成的特异性限速酶。雌激素受体（ER）β激动剂已被证明可减轻啮齿动物模型中的焦虑和绝望样行为。因此，我们通过检测选择性ERβ激动剂二芳基丙腈（DPN）全身和局部应用对tph2 mRNA表达的影响，来验证ERβ可能参与调节中缝背核（DRN）5-HT神经元基因表达的假说。对去卵巢（OVX）雌性大鼠皮下注射DPN或溶剂，每日1次，共8天。原位杂交显示，全身给予DPN可提高尾侧和中背侧DRN的基础tph2 mRNA表达。在治疗第6天和第7天，对所有动物进行旷场试验（OF）和高架十字迷宫试验（EPM），行为测试证实了ERβ激活具有抗焦虑特性。另一组雌性OVX大鼠双侧立体定位植入含激素的蜡丸，置于DRN两侧。蜡丸含17-β-雌二醇（E）、DPN或不含激素。DPN和E均显著增强中背侧DRN的tph2 mRNA表达。DPN还增加了尾侧DRN的tph2 mRNA。DPN和E处理的大鼠在强迫游泳试验（FST）中表现出更积极的应激应对行为。在OF或EPM中未发现行为差异。这些数据表明，ERβ在大鼠DRN水平发挥作用，调节tph2 mRNA表达，从而影响DRN亚区域的5-HT合成。我们的结果还表明，DRN中ERβ神经元的局部激活可能足以减少绝望样行为，但不能减少抗焦虑行为。
