Célia Moreira Borella Vládia, Seeman Mary V, Carneiro Cordeiro Rafaela, Vieira dos Santos Júnia, Romário Matos de Souza Marcos, Nunes de Sousa Fernandes Ethel, Santos Monte Aline, Maria Mendes Vasconcelos Silvânia, Quinn John P, de Lucena David F, Carvalho André F, Macêdo Danielle
Department of Physiology and Pharmacology, Drug Research and Development Center, Faculty of Medicine, Neuropharmacology Laboratory, Federal University of Ceara, Fortaleza, CE, Brazil.
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Dev Neurobiol. 2016 May;76(5):519-32. doi: 10.1002/dneu.22329. Epub 2015 Aug 6.
Neonatal N-methyl-D-aspartate (NMDA) receptor blockade in rodents triggers schizophrenia (SCZ)-like alterations during adult life. SCZ is influenced by gender in age of onset, premorbid functioning, and course. Estrogen, the hormone potentially driving the gender differences in SCZ, is known to present neuroprotective effects such as regulate oxidative pathways and the expression of brain-derived neurotrophic factor (BDNF). Thus, the aim of this study was to verify if differences in gender and/or estrous cycle phase during adulthood would influence the development of behavioral and neurochemical alterations in animals neonatally administered ketamine. The results showed that ketamine-treated male (KT-male) and female-in-diestrus (KTF-diestrus, the low estrogen phase) presented significant deficits in prepulse inhibition of the startle reflex and spatial working memory, two behavioral SCZ endophenotypes. On the contrary, female ketamine-treated rats during proestrus (KTF-proestrus, the high estradiol phase) had no behavioral alterations. This correlated with an oxidative imbalance in the hippocampus (HC) of both male and KTF-diestrus female rats, that is, decreased levels of GSH and increased levels of lipid peroxidation and nitrite. Similarly, BDNF was decreased in the KTF-diestrus rats while no alterations were observed in KTF-proestrus and male animals. The changes in the HC were in contrast to those in the prefrontal cortex in which only increased levels of nitrite in all groups studied were observed. Thus, there is a gender difference in the adult rat HC in response to ketamine neonatal administration, which is based on the estrous cycle. This is discussed in relation to neuropsychiatric conditions and in particular SCZ.
啮齿动物新生儿期N-甲基-D-天冬氨酸（NMDA）受体阻断会在成年期引发精神分裂症（SCZ）样改变。SCZ在发病年龄、病前功能和病程方面受性别影响。雌激素是可能导致SCZ性别差异的激素，已知具有神经保护作用，如调节氧化途径和脑源性神经营养因子（BDNF）的表达。因此，本研究的目的是验证成年期的性别差异和/或发情周期阶段是否会影响新生期给予氯胺酮的动物行为和神经化学改变的发展。结果表明，氯胺酮处理的雄性（KT-雄性）和处于间情期的雌性（KTF-间情期，低雌激素阶段）在惊吓反射的前脉冲抑制和空间工作记忆方面存在显著缺陷，这是两种行为学SCZ内表型。相反，处于发情前期的氯胺酮处理雌性大鼠（KTF-发情前期，高雌二醇阶段）没有行为改变。这与雄性和KTF-间情期雌性大鼠海马体（HC）中的氧化失衡相关，即谷胱甘肽水平降低、脂质过氧化和亚硝酸盐水平升高。同样，KTF-间情期大鼠的BDNF降低，而KTF-发情前期和雄性动物未观察到改变。HC中的变化与前额叶皮质相反，在前额叶皮质中，仅观察到所有研究组中亚硝酸盐水平升高。因此，成年大鼠HC对新生儿期给予氯胺酮的反应存在基于发情周期的性别差异。本文就此与神经精神疾病尤其是SCZ进行了讨论。
