Gender and estrous cycle influences on behavioral and neurochemical alterations in adult rats neonatally administered ketamine |
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Authors: | Vládia Célia Moreira Borella Mary V Seeman Rafaela Carneiro Cordeiro Júnia Vieira dos Santos Marcos Romário Matos de Souza Ethel Nunes de Sousa Fernandes Aline Santos Monte Silvânia Maria Mendes Vasconcelos John P Quinn David F de Lucena André F Carvalho Danielle Macêdo |
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Institution: | 1. Department of Physiology and Pharmacology, Drug Research and Development Center, Faculty of Medicine, Neuropharmacology Laboratory, Federal University of Ceara, Fortaleza, CE, Brazil;2. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada;3. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, United Kingdom;4. Department of Clinical Medicine, Psychiatry Research Group, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil |
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Abstract: | 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. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 519–532, 2016 |
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Keywords: | schizophrenia ketamine neurodevelopmental model gender differences brain‐derived neurotrophic factor oxidative and nitrosative stress hippocampus |
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