Open-field behavior of rats previously subjected to short-term hyperbilirubinemia with or without blood-brain barrier manipulations.

The aim of this study was to investigate (i) whether bilirubin encephalopathy with lasting sequelae could be created in a rat model, and (ii) putative differences in brain toxicity between bound and unbound bilirubin. Hyperbilirubinemia was produced by infusing bilirubin 20 mg/kg/h during 3 h into 6-week-old male Sprague-Dawley rats. In addition to the hyperbilirubinemia, different groups were created by exposing the rats to hyperosmolality, hypercarbia, and sulfisoxazole. Three weeks after the infusion the rats were studied in an open-field apparatus during 10 daily sessions of 15 min duration. A data collection program was used to study the following measures of activity: crossings in cage, peeks, rearing, latency to enter field, crossings in middle and in outer field, and time outside cage. The data were subjected to multivariate analyses of variance (MANOVA). Generally, the level of activity was higher in the bilirubin-treated rats as compared to the control animals. The difference in activity between bilirubin-treated and control rats changed systematically both between and within sessions. The data show that both unbound and albumin-bound bilirubin are neurotoxic, but they indicate a more pronounced effect of unbound bilirubin. The sequelae of bilirubin brain toxicity appear to include changes in stimulus processing. This is compatible with findings from neuropsychological tests of children who have had significant neonatal hyperbilirubinemia.