Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS 66045, United States.
Psychoneuroendocrinology. 2013 Jul;38(7):1145-57. doi: 10.1016/j.psyneuen.2012.11.005. Epub 2012 Dec 5.
A major problem with current anti-depressant therapy is that it takes on average 6-7 weeks for remission. Since desensitization of serotonin (5-HT)1A receptor signaling contributes to the anti-depressive response, acceleration of the desensitization may reduce this delay in response to antidepressants. The purpose of the present study was to test the hypothesis that estradiol accelerates fluoxetine-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the hypothalamus (PVN) of rats, via alterations in components of the 5-HT1A receptor signaling pathway. Ovariectomized rats were injected with estradiol and/or fluoxetine, then adrenocorticotropic hormone (ACTH) and oxytocin responses to a 5-HT1A receptor agonist (+)-8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) were examined to assess the function of 5-HT1A receptors in the PVN. Treatment with estradiol for either 2 or 7 days or fluoxetine for 2 days produced at most a partial desensitization of 5-HT1A receptor signaling, whereas 7 days of fluoxetine produced full desensitization. Combined treatment with estradiol and fluoxetine for 2 days produced nearly a full desensitization, demonstrating an accelerated response compared to either treatment alone. With two days of combined treatments, estradiol prevented the fluoxetine-induced increase in 5-HT1A receptor protein, which could contribute to the more rapid desensitization. Furthermore, EB treatment for 2 days decreased the abundance of the 35 kD Gαz protein which could contribute to the desensitization response. We found two isoforms of Gαz proteins with molecular mass of 35 and 33 kD, which differentially distributed in the detergent resistant microdomain (DRM) and in Triton X-100 soluble membrane region, respectively. The 35 kD Gαz proteins in the DRM can be sumoylated by SUMO1. Stimulation of 5-HT1A receptors with 8-OH-DPAT increases the sumoylation of Gαz proteins and reduces the 33 kD Gαz proteins, suggesting that these responses may be related to the desensitization of 5-HT1A receptors. Treatment with estradiol for 2 days also reduced the levels of the G-protein coupled estrogen receptor GPR30, possibly limiting to the ability of estradiol to produce only a partial desensitization response. These data provide evidence that estradiol may be effective as a short-term adjuvant to SSRIs to accelerate the onset of therapeutic effects.
目前抗抑郁治疗的一个主要问题是缓解期平均需要 6-7 周。由于 5-羟色胺（5-HT）1A 受体信号脱敏有助于抗抑郁反应，加速脱敏可能会缩短抗抑郁药的反应时间。本研究的目的是通过改变 5-HT1A 受体信号通路的组成部分，测试雌二醇是否通过加速 5-HT1A 受体信号脱敏来加速氟西汀在大鼠下丘脑室旁核（PVN）中的作用。给去卵巢大鼠注射雌二醇和/或氟西汀，然后用 5-HT1A 受体激动剂（+）-8-羟基-2-二丙基氨基四氢萘（8-OH-DPAT）检测促肾上腺皮质激素（ACTH）和催产素的反应，以评估 5-HT1A 受体在 PVN 中的功能。用雌二醇治疗 2 或 7 天或氟西汀治疗 2 天最多只能使 5-HT1A 受体信号部分脱敏，而氟西汀治疗 7 天则完全脱敏。雌二醇和氟西汀联合治疗 2 天即可产生几乎完全脱敏，与单独治疗相比表现出更快的反应。用两天联合治疗，雌二醇阻止了氟西汀引起的 5-HT1A 受体蛋白增加，这可能有助于更快的脱敏。此外，EB 治疗 2 天可减少 35 kD Gαz 蛋白的丰度，这可能有助于脱敏反应。我们发现了两种分子量为 35 和 33 kD 的 Gαz 蛋白同工型，它们分别在去污剂抗性微区（DRM）和 Triton X-100 可溶性膜区分布不同。DRM 中的 35 kD Gαz 蛋白可被 SUMO1 SUMOylation。用 8-OH-DPAT 刺激 5-HT1A 受体可增加 Gαz 蛋白的 SUMOylation，并减少 33 kD Gαz 蛋白，提示这些反应可能与 5-HT1A 受体的脱敏有关。雌二醇治疗 2 天也降低了 G 蛋白偶联雌激素受体 GPR30 的水平，这可能限制了雌二醇仅产生部分脱敏反应的能力。这些数据提供了证据，表明雌二醇可能作为 SSRIs 的短期辅助治疗，加速治疗效果的出现。
