RESUMEN
Sex differences in the immune response can also affect the febrile response, particularly the fever induced by lipopolysaccharide (LPS). However, other pathogen-associated molecular patterns, such as zymosan A (Zym) and polyinosinic-polycytidylic acid (Poly I:C), also induce fever in male rats with a different time course of cytokine release and different mediators such as endothelin-1 (ET-1). This study investigated whether female sex hormones affect Zym- and Poly I:C-induced fever and the involvement of ET-1 in this response. The fever that was induced by Zym and Poly I:C was higher in ovariectomized (OVX) female rats compared with sham-operated female rats. Estrogen replacement in OVX females reduced Zym- and Poly I:C-induced fever. The ETB receptor antagonist BQ788 reversed the LPS-induced fever in cycling females but not in OVX females. BQ788 did not alter the fever that was induced by Zym or Poly I:C in either cycling or OVX females. These findings suggest that the febrile response in cycling females is lower, independently of the stimulus that is inducing it and is probably controlled by estrogen. Also, ET-1 seems to participate in the febrile response that was induced by LPS in males and cycling females but not in the LPS-induced fever in OVX females. Additionally, ET-1 was not involved in the febrile response that was induced by Zym or Poly I:C in females.
Asunto(s)
Endotelina-1/metabolismo , Fiebre/inducido químicamente , Fiebre/metabolismo , Hormonas Esteroides Gonadales/metabolismo , Poli I-C/toxicidad , Zimosan/toxicidad , Animales , Endotelina-1/antagonistas & inhibidores , Femenino , Inyecciones Intraventriculares , Masculino , Ovariectomía/tendencias , Poli I-C/administración & dosificación , Ratas , Ratas Wistar , Zimosan/administración & dosificaciónRESUMEN
Maternal immune activation (MIA) during pregnancy in rodents increases the risk of the offspring to develop schizophrenia-related behaviors, suggesting a relationship between the immune system and the brain development. Here we tested the hypothesis that MIA induced by the viral mimetic polyinosinic-polycytidylic acid (poly I:C) in early or late gestation of mice leads to behavioral and neuroanatomical disorders in the adulthood. On gestational days (GDs) 9 or 17 pregnant dams were treated with poly I:C or saline via intravenous route and the offspring behaviors were measured during adulthood. Considering the progressive structural neuroanatomical alterations in the brain of individuals with schizophrenia, we used magnetic resonance imaging (MRI) to perform brain morphometric analysis of the offspring aged one year. MIA on GD9 or GD17 led to increased basal locomotor activity, enhanced motor responses to ketamine, a psychotomimetic drug, and reduced time spent in the center of the arena, suggesting an increased anxiety-like behavior. In addition, MIA on GD17 reduced glucose preference in the offspring. None of the treatments altered the relative volume of the lateral ventricles. However, a decrease in brain volume, especially for posterior structures, was observed for one-year-old animals treated with poly I:C compared with control groups. Thus, activation of the maternal immune system at different GDs lead to neuroanatomical and behavioral alterations possibly related to the positive and negative symptoms of schizophrenia. These results provide insights on neuroimmunonological and neurodevelopmental aspects of certain psychopathologies, such as schizophrenia.
Asunto(s)
Encéfalo/patología , Trastornos Mentales/etiología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Esquizofrenia/complicaciones , Esquizofrenia/etiología , Esquizofrenia/patología , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Encéfalo/diagnóstico por imagen , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Modelos Animales de Enfermedad , Embrión de Mamíferos , Femenino , Preferencias Alimentarias , Inductores de Interferón/toxicidad , Ketamina/toxicidad , Locomoción/fisiología , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Poli I-C/toxicidad , Embarazo , Esquizofrenia/diagnóstico por imagen , Sacarosa/administración & dosificaciónRESUMEN
BACKGROUND: Prenatal environmental adversities may affect brain development and are associated with increased risk for schizophrenia, an illness with 50% comorbidity with addiction. Maternal immune activation by poly-inosinic-citidilic acid (Poly(I:C)) exposure can promote behavioral alterations consistent with schizophrenia symptoms in rodents. OBJECTIVES: Considering the vulnerability to addiction in patients with schizophrenia, we evaluated the interactions between prenatal Poly(I:C) administration and addiction in two animal models (behavioral sensitization and conditioned place preference - CPP) in mice repeatedly treated with amphetamine (AMP). Additionally, stereotyped behavior and cross-sensitization with cocaine (COC) were also investigated. METHODS: Swiss male mice offspring were submitted to prenatal administration of 5mg/kg Poly(I:C) in the 9(th) day of pregnancy. At the age of 90days, mice were treated with 2.5mg/kg AMP for 9days to evaluate behavioral sensitization or stereotyped behavior. Cross-sensitization with 10mg/kg COC was evaluated 24h after the last treatment day. For AMP-induced CPP evaluation, mice were treated during 8 consecutive days. RESULTS: Prenatal Poly(I:C) administration potentiated both AMP-induced behavioral sensitization and CPP. Furthermore, Poly(I:C) increased cross-sensitization with COC. CONCLUSIONS: Prenatal administration of Poly(I:C) is able to potentiate vulnerability to addiction in two animal models, without however modulating stereotyped behavior.
Asunto(s)
Trastornos Relacionados con Anfetaminas/etiología , Trastornos Relacionados con Anfetaminas/inmunología , Conducta Exploratoria/fisiología , Poli I-C/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Animales , Cocaína/toxicidad , Condicionamiento Psicológico/fisiología , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Femenino , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Embarazo , Conducta Estereotipada/fisiología , Factores de TiempoRESUMEN
The present study evaluated the involvement of interleukin(IL)-1ß, tumor necrosis factor-α (TNF-α), IL-6, interferon(IFN)-γ, prostaglandins of the E2 series, endothelins, substance P and opioids within the central nervous system in polyinosinic:polycytidylic acid (Poly I:C)-induced fever in rats. Poly I:C injection induced a febrile response which was reduced by intracerebroventricular administration of the antibodies against TNF-α, IL-6, or IFN-γ, or by IL-1 or µ receptor antagonists. Intraperitoneal injection of indomethacin or oral administration of celecoxib also reduced Poly I:C-induced fever. Poly I:C increased prostaglandin E2 levels in the cerebrospinal fluid of the animals which was also reduced by indomethacin. The intracerebroventricular injection of ETB or NK1 receptor antagonists did not alter Poly I:C-induced fever. These data suggest the involvement of IL-1ß, TNF-α, IL-6, IFN-γ, prostaglandin E2, and opioids but not endothelins and substance P on Poly I:C-induced fever.