Xu H, Qin S, Carrasco G A, Dai Y, Filardo E J, Prossnitz E R, Battaglia G, Doncarlos L L, Muma N A
Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago School of Medicine, Maywood, IL 60153, USA.
Neuroscience. 2009 Feb 18;158(4):1599-607. doi: 10.1016/j.neuroscience.2008.11.028. Epub 2008 Nov 21.
Selective serotonin reuptake inhibitors (SSRIs), such as Prozac, are used to treat mood disorders. SSRIs attenuate (i.e. desensitize) serotonin 1A (5-HT(1A)) receptor signaling, as demonstrated in rats through decreased release of oxytocin and adrenocorticotropin hormone (ACTH) following 5-HT(1A) receptor stimulation. Maximal therapeutic effects of SSRIs for treatment of mood disorders, as well as effects on hypothalamic 5-HT(1A) receptor signaling in animals, take 1 to 2 weeks to develop. Estradiol also attenuates 5-HT(1A) receptor signaling, but, in rats, these effects occur within 2 days; thus, estrogens or selective estrogen receptor modulators may serve as useful short-term tools to accelerate desensitization of 5-HT(1A) receptors in response to SSRIs if candidate estrogen receptor targets in the hypothalamus are identified. We found high levels of GPR30, which has been identified recently as a pertussis-toxin (PTX) sensitive G-protein-coupled estrogen receptor, in the hypothalamic paraventricular nucleus (PVN) of rats. Double-label immunohistochemistry revealed that GPR30 co-localizes with 5-HT(1A) receptors, corticotrophin releasing factor (CRF) and oxytocin in neurons in the PVN. Pretreatment with PTX to the PVN before peripheral injections of 17-beta-estradiol 3-benzoate completely prevented the reduction of the oxytocin response to the 5-HT(1A) receptor agonist, (+)-8-hydroxy-2-dipropylaminotetralin (DPAT). Treatment with the selective GRP30 agonist, G-1, attenuated 5-HT(1A) receptor signaling in the PVN as measured by an attenuated oxytocin (by 29%) and ACTH (by 31%) response to DPAT. This study indicates that a putative extra-nuclear estrogen receptor, GPR30, may play a role in estradiol-mediated attenuation of 5-HT(1A) receptor signaling, and potentially in accelerating the effects of SSRIs in treatment of mood disorders.
选择性5-羟色胺再摄取抑制剂（SSRI），如百忧解，被用于治疗情绪障碍。SSRI会减弱（即脱敏）5-羟色胺1A（5-HT(1A)）受体信号传导，正如在大鼠实验中所证实的，5-HT(1A)受体受到刺激后，催产素和促肾上腺皮质激素（ACTH）的释放会减少。SSRI治疗情绪障碍的最大治疗效果以及对动物下丘脑5-HT(1A)受体信号传导的影响需要1至2周才能显现。雌二醇也会减弱5-HT(1A)受体信号传导，但在大鼠中，这些影响在2天内就会出现；因此，如果能确定下丘脑的候选雌激素受体靶点，雌激素或选择性雌激素受体调节剂可能会成为有用的短期工具，以加速5-HT(1A)受体对SSRI产生的脱敏反应。我们发现大鼠下丘脑室旁核（PVN）中存在高水平的GPR30，它最近被鉴定为一种对百日咳毒素（PTX）敏感的G蛋白偶联雌激素受体。双重标记免疫组织化学显示，GPR30与PVN神经元中的5-HT(1A)受体、促肾上腺皮质激素释放因子（CRF）和催产素共定位。在经外周注射17-β-雌二醇3-苯甲酸酯之前，先对PVN进行PTX预处理，可完全防止催产素对5-HT(CA)受体激动剂（+）-8-羟基-2-二丙基氨基四氢萘（DPAT）的反应降低。用选择性GRP30激动剂G-1进行治疗，可减弱PVN中的5-HT(1A)受体信号传导，这通过催产素（降低29%）和ACTH（降低31%）对DPAT的反应减弱来衡量。这项研究表明，一种假定的核外雌激素受体GPR30可能在雌二醇介导的5-HT(1A)受体信号传导减弱中发挥作用，并可能在加速SSRI治疗情绪障碍的效果方面发挥作用。
