De Jesús-Burgos María I, González-García Stephanie, Cruz-Santa Yanira, Pérez-Acevedo Nivia L
Department of Biology, University of Puerto Rico, Cayey Campus, PO Box 372230, Cayey, PR 00737-2230, USA.
Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, PR 00931, USA.
Behav Brain Res. 2016 Apr 1;302:200-12. doi: 10.1016/j.bbr.2016.01.009. Epub 2016 Jan 8.
Women are more susceptible than men to develop anxiety disorders, however, the mechanisms involved are still unclear. In this study, we investigated the role of group I metabotropic glutamate receptors (mGluRs), a target for anxiety disorders, and whether estradiol may modulate conflict-based anxiety in female rats by using the Vogel Conflict Test (VCT). We used ovariectomized female rats with high (OVX+EB) and low (OVX) estradiol levels and intact male rats to evaluate sex differences. Infusion of (S)-3,5-Dihydroxyphenylglycine (DHPG), a group I mGluR agonist, into the basolateral amygdala, a region involved in anxiety-responses, statistically increased the number of shocks in OVX, but not OVX+EB female rats at 0.1, nor at 1.0 μM. In contrast, DHPG statistically decreased the number of shocks in male rats at 1.0 μM only. DHPG (0.1 μM) increased the number of recoveries in OVX, but not OVX+EB or male rats. Sex differences were detected for the number of shocks, recoveries and punished licks, where female rats displayed more conflict than male rats. Western blot analyses showed that protein expression of mGluR1, but not mGluR5 was higher in OVX+EB>OVX>male rats in the amygdala, whereas no significant differences were detected in the hippocampus, olfactory bulb and/or the periaqueductal gray. Therefore, DHPG produced paradoxical effects that are sex dependent; producing anxiolytic-like effects in female rats, while anxiogenic-like effects in male rats according to the VCT. These results highlight the importance of including female experimental models to underpin the neural circuitry of anxiety according to sex and for the screening of novel anxiolytic compounds.
女性比男性更容易患上焦虑症，然而，其中涉及的机制仍不清楚。在本研究中，我们通过使用 Vogel 冲突试验（VCT），研究了 I 型代谢型谷氨酸受体（mGluRs）（一种焦虑症治疗靶点）的作用，以及雌二醇是否可以调节雌性大鼠基于冲突的焦虑。我们使用了高雌二醇水平（OVX+EB）和低雌二醇水平（OVX）的去卵巢雌性大鼠以及完整雄性大鼠来评估性别差异。将 I 型 mGluR 激动剂（S）-3,5-二羟基苯甘氨酸（DHPG）注入参与焦虑反应的基底外侧杏仁核，在 0.1 μM 和 1.0 μM 时，统计学上增加了 OVX 雌性大鼠的电击次数，但对 OVX+EB 雌性大鼠没有影响。相比之下，仅在 1.0 μM 时，DHPG 统计学上减少了雄性大鼠的电击次数。DHPG（0.1 μM）增加了 OVX 雌性大鼠的恢复次数，但对 OVX+EB 雌性大鼠或雄性大鼠没有影响。在电击次数、恢复次数和受罚舔舐次数方面检测到了性别差异，雌性大鼠比雄性大鼠表现出更多的冲突。蛋白质免疫印迹分析表明，杏仁核中 mGluR1 的蛋白表达在 OVX+EB>OVX>雄性大鼠中较高，而 mGluR5 则无此现象，而在海马体、嗅球和/或导水管周围灰质中未检测到显著差异。因此，DHPG 产生了与性别相关的矛盾效应；根据 VCT，在雌性大鼠中产生抗焦虑样效应，而在雄性大鼠中产生致焦虑样效应。这些结果突出了纳入雌性实验模型以根据性别确定焦虑神经回路并筛选新型抗焦虑化合物的重要性。
