title: Gender and estrous cycle influences on behavioral and neurochemical alterations in adult rats neonatally administered ketamine.
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.
authors.affiliation: Department of Physiology and Pharmacology, Drug Research and Development Center, Faculty of Medicine, Neuropharmacology Laboratory, Federal University of Ceara, Fortaleza, CE, Brazil.
authors.forename: Vládia
authors.initials: V
authors.lastname: Célia Moreira Borella
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Seeman
authors.affiliation: Department of Physiology and Pharmacology, Drug Research and Development Center, Faculty of Medicine, Neuropharmacology Laboratory, Federal University of Ceara, Fortaleza, CE, Brazil.
authors.forename: Rafaela
authors.initials: R
authors.lastname: Carneiro Cordeiro
authors.affiliation: Department of Physiology and Pharmacology, Drug Research and Development Center, Faculty of Medicine, Neuropharmacology Laboratory, Federal University of Ceara, Fortaleza, CE, Brazil.
authors.forename: Júnia
authors.initials: J
authors.lastname: Vieira dos Santos
authors.affiliation: Department of Physiology and Pharmacology, Drug Research and Development Center, Faculty of Medicine, Neuropharmacology Laboratory, Federal University of Ceara, Fortaleza, CE, Brazil.
authors.forename: Marcos
authors.initials: M
authors.lastname: Romário Matos de Souza
authors.affiliation: Department of Physiology and Pharmacology, Drug Research and Development Center, Faculty of Medicine, Neuropharmacology Laboratory, Federal University of Ceara, Fortaleza, CE, Brazil.
authors.forename: Ethel
authors.initials: E
authors.lastname: Nunes de Sousa Fernandes
authors.affiliation: Department of Physiology and Pharmacology, Drug Research and Development Center, Faculty of Medicine, Neuropharmacology Laboratory, Federal University of Ceara, Fortaleza, CE, Brazil.
authors.forename: Aline
authors.initials: A
authors.lastname: Santos Monte
authors.affiliation: Department of Physiology and Pharmacology, Drug Research and Development Center, Faculty of Medicine, Neuropharmacology Laboratory, Federal University of Ceara, Fortaleza, CE, Brazil.
authors.forename: Silvânia
authors.initials: S
authors.lastname: Maria Mendes Vasconcelos
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Quinn
authors.affiliation: Department of Physiology and Pharmacology, Drug Research and Development Center, Faculty of Medicine, Neuropharmacology Laboratory, Federal University of Ceara, Fortaleza, CE, Brazil.
authors.forename: David F
authors.initials: DF
authors.lastname: de Lucena
authors.affiliation: Department of Clinical Medicine, Psychiatry Research Group, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil.
authors.forename: André F
authors.initials: AF
authors.lastname: Carvalho
authors.affiliation: Department of Physiology and Pharmacology, Drug Research and Development Center, Faculty of Medicine, Neuropharmacology Laboratory, Federal University of Ceara, Fortaleza, CE, Brazil.
authors.forename: Danielle
authors.initials: D
authors.lastname: Macêdo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004195:Disease Models, Animal; D058068:Endophenotypes; D030762:Estrous Cycle / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000503:physiopathology; D007649:Ketamine / Q000008:administration & dosage* / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D009573:Nitrites / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000254:growth & development / Q000503:physiopathology; D065808:Prepulse Inhibition / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D017208:Rats, Wistar; D012559:Schizophrenia; D012727:Sex Characteristics; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009573:Nitrites; D007649:Ketamine
keywords: brain-derived neurotrophic factor; gender differences; hippocampus; ketamine; neurodevelopmental model; oxidative and nitrosative stress; schizophrenia