Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Greece; First Department of Psychiatry, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Greece.
Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Greece.
Psychoneuroendocrinology. 2018 Jan;87:93-107. doi: 10.1016/j.psyneuen.2017.10.007. Epub 2017 Oct 10.
Aromatase inhibitors, which are widely used for the treatment of estrogen-dependent cancers, have been associated with psychiatric side effects ranging from mania to depression. In the present study, we investigated sex differences in the behavioral and neurochemical effects of aromatase inhibition on male and female, sham-operated or gonadectomized adult rats. Three weeks after surgery, rats received chronic treatment with the aromatase inhibitor letrozole or vehicle and were then subjected to the open field test, which assesses general activity. Half of the subjects were subsequently exposed to the stressful procedure of the forced swim test (FST), which is also a test of antidepressant activity. Aromatase activity was analyzed in the hypothalamus and testosterone and corticosterone were assayed in the blood serum of all rats. The hippocampus and prefrontal cortex (PFC) were analyzed for monoamine (noradrenaline, dopamine and serotonin), as well as amino acid (GABA, glutamate, glycine, taurine, alanine and histidine) levels. The observed decrease in hypothalamic aromatase activity confirmed the efficacy of letrozole treatment in both sexes. Moreover, letrozole enhanced testosterone levels in sham-operated females. In the open field test, females were overall more active and explorative than males and gonadectomy eliminated this sex difference. In the FST, females exhibited overall higher immobility than males and gonadectomy further enhanced this passive behavior in both sexes. However, sustained aromatase inhibition had no effect on open field and FST behaviors. Head shakes during FST, which were fewer in females than in males, were reduced by castration in males and by letrozole treatment in ovariectomized females, suggesting a role of testosterone and extra-gonadal estrogens in the expression of this behavior. Sustained aromatase inhibition also decreased noradrenaline and the dopaminergic turnover rates [DOPAC/DA, HVA/DA] in the hippocampus and PFC of male and female rats, irrespectively of gonadectomy. Moreover, letrozole treatment enhanced the serotonergic turnover [5HIAA/5HT] rate in the hippocampus of males and females, irrespectively of gonadectomy. Amino acid levels were not influenced by letrozole, but sex differences were demonstrated with higher levels in the PFC of females vs. males. Present findings suggest that the neuropsychiatric effects of aromatase inhibition can be attributed to the inhibition of extragonadal estrogen synthesis, presumably in the brain, and could be further associated with serotonergic and catecholaminergic changes in brain regions involved in mood and cognition. Importantly, present data could be linked with the neurobiology of affective side-effects in post-menopausal women receiving aromatase inhibitors.
芳香酶抑制剂被广泛用于治疗雌激素依赖性癌症，其与从躁狂到抑郁等各种精神副作用相关。在本研究中，我们研究了芳香酶抑制对去势或性腺切除术成年雄性和雌性大鼠的行为和神经化学影响的性别差异。手术后 3 周，大鼠接受了芳香酶抑制剂来曲唑或载体的慢性治疗，然后进行了旷场测试，以评估其一般活动。其中一半的动物随后暴露于强迫游泳测试（FST）的应激程序中，这也是一种抗抑郁活性测试。分析了所有大鼠下丘脑的芳香酶活性以及血清中的睾酮和皮质酮。还分析了海马体和前额皮质（PFC）中单胺（去甲肾上腺素、多巴胺和 5-羟色胺）以及氨基酸（GABA、谷氨酸、甘氨酸、牛磺酸、丙氨酸和组氨酸）水平。观察到的下丘脑芳香酶活性下降证实了来曲唑治疗在两性中的疗效。此外，来曲唑增加了去势雌性的睾酮水平。在旷场测试中，雌性动物通常比雄性动物更活跃和探索性，而去势消除了这种性别差异。在 FST 中，雌性动物的不动性总体上高于雄性动物，而去势进一步增强了两性的这种被动行为。然而，持续的芳香酶抑制对旷场和 FST 行为没有影响。FST 期间的摇头，雌性动物比雄性动物少，在雄性动物中去势减少，在去势雌性动物中用来曲唑治疗减少，这表明睾酮和外周雌激素在表达这种行为中的作用。持续的芳香酶抑制也降低了雄性和雌性大鼠海马体和前额皮质中的去甲肾上腺素和多巴胺能代谢物（DOPAC/DA、HVA/DA）的周转率，与去势无关。此外，来曲唑治疗增强了雄性和雌性海马体中的 5-羟色胺能代谢物（5HIAA/5HT）周转率，与去势无关。来曲唑治疗不影响氨基酸水平，但表现出性别差异，即雌性 PFC 中的水平高于雄性。本研究结果表明，芳香酶抑制的神经精神作用可归因于外周雌激素合成的抑制，推测是在大脑中，并且可能与参与情绪和认知的大脑区域中的 5-羟色胺能和儿茶酚胺能变化进一步相关。重要的是，目前的数据可以与接受芳香酶抑制剂的绝经后妇女的情感副作用的神经生物学联系起来。
