RESUMEN
Recent evidence suggests that sickness behaviors following lipopolysaccharide (LPS)-treatment may be modulated by environmental factors such as the light-dark (LD) cycle. The present study characterized LPS-induced hypoactivity and behavioral tolerance development across individual phases of the light-dark cycle and the transitions between phases. On days 1, 4 and 7, male rats were treated with LPS (200microg/kg i.p.) or saline 30min prior to the onset of either the dark period (dark-tested group) or the light period (light-tested group). Following treatment, rats were placed in non-novel automated open-fields where various aspects of locomotor activity were monitored for 16h. On day 1, LPS-treated rats in both the dark and light tested groups showed significant hypoactivity. However, temporal differences in the onset of hypoactivity were observed between the groups. In dark tested animals significant hypoactivity started 60min after LPS treatment and continued until the light period when hypoactivity was diminished. In contrast, the light tested LPS-treated animals did not exhibit a prolonged period of hypoactivity until the transition between the light and dark periods, 750min following LPS injection. On days 4 and 7, light tested animals showed complete tolerance to LPS as evidenced by the absence of significant activity reductions, whereas dark tested animals continued to show significant periods of hypoactivity. These results indicate that there are day-night differences in both the initial LPS-induced hypoactivity response as well as behavioral tolerance development. The rate of tolerance development to LPS may be a critical factor to survival and the prevention of sepsis, as organisms are repeatedly exposed to pathogens across the life cycle.
Asunto(s)
Ritmo Circadiano/fisiología , Tolerancia a Medicamentos/fisiología , Lipopolisacáridos/farmacología , Actividad Motora/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Masculino , Análisis Multivariante , Ratas , Ratas Long-Evans , Factores de TiempoRESUMEN
Clinical observations suggest that certain gut and dietary factors may transiently worsen symptoms in autism spectrum disorders (ASD), epilepsy and some inheritable metabolic disorders. Propionic acid (PPA) is a short chain fatty acid and an important intermediate of cellular metabolism. PPA is also a by-product of a subpopulation of human gut enterobacteria and is a common food preservative. We examined the behavioural, electrophysiological, neuropathological, and biochemical effects of treatment with PPA and related compounds in adult rats. Intraventricular infusions of PPA produced reversible repetitive dystonic behaviours, hyperactivity, turning behaviour, retropulsion, caudate spiking, and the progressive development of limbic kindled seizures, suggesting that this compound has central effects. Biochemical analyses of brain homogenates from PPA treated rats showed an increase in oxidative stress markers (e.g., lipid peroxidation and protein carbonylation) and glutathione S-transferase activity coupled with a decrease in glutathione and glutathione peroxidase activity. Neurohistological examinations of hippocampus and adjacent white matter (external capsule) of PPA treated rats revealed increased reactive astrogliosis (GFAP immunoreactivity) and activated microglia (CD68 immunoreactivity) suggestive of a neuroinflammatory process. This was coupled with a lack of cytotoxicity (cell counts, cleaved caspase 3' immunoreactivity), and an increase in phosphorylated CREB immunoreactivity. We propose that some types of autism may be partial forms of genetically inherited or acquired disorders involving altered PPA metabolism. Thus, intraventricular administration of PPA in rats may provide a means to model some aspects of human ASD in rats.
Asunto(s)
Trastorno Autístico/fisiopatología , Encéfalo/fisiopatología , Conducta Exploratoria , Ácidos Grasos Volátiles/metabolismo , Propionatos/metabolismo , Animales , Trastorno Autístico/inducido químicamente , Trastorno Autístico/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Ácidos Grasos Volátiles/administración & dosificación , Ácidos Grasos Volátiles/toxicidad , Hipocampo/metabolismo , Hipocampo/patología , Hipocampo/fisiopatología , Inyecciones Intraventriculares , Excitación Neurológica/patología , Masculino , Actividad Motora , Neocórtex/metabolismo , Neocórtex/fisiopatología , Neostriado/metabolismo , Neostriado/patología , Neostriado/fisiopatología , Estrés Oxidativo , Propionatos/administración & dosificación , Propionatos/toxicidad , Distribución Aleatoria , Ratas , Ratas Long-EvansRESUMEN
RATIONALE: Although the behavioral effects of systemic injection of lipopolysaccharide (LPS) have been extensively investigated, the modulation of these effects by natural environmental factors has received little attention. OBJECTIVES: The present study investigated whether or not locomotor activity reductions and the development of behavioral tolerance in response to LPS treatment would occur to the same degree if male and female rats were treated with LPS at four distinct time points across the light-dark (LD) cycle. METHODS: On day 1, male and female rats were injected with either LPS (200 microg/kg IP) or saline at light onset (0400 hours), 2 h into light period (0600 hours), at dark onset (1600 hours) or 2 h into the dark period (1800 hours). Two hours after injection, rats were placed in non-novel, automated open-fields and locomotor activity was assessed. The development of behavioral tolerance to LPS was evaluated three days later (day 4) using the same procedure. RESULTS: On day 1, LPS-treated animals displayed robust activity decrements during the light period with males displaying greater reductions than females. During the dark period, LPS-treated animals showed a similar hypoactivity response. After LPS treatment on day 4, all rats exhibited some behavioral tolerance to LPS. Rats given LPS treatment at light onset and during the dark period showed complete tolerance development while LPS-treated rats during the light phase at dark onset showed incomplete tolerance, still displaying significant reductions in some activity variables. CONCLUSIONS: It appears that the magnitude of hypoactivity and the development of behavioral tolerance in response to LPS depend on the phase of the LD cycle during which it is administered.