Abstracts

Rationale: Children with epilepsy are significantly more likely than the general population to have hyperactivity, attentional impairments, and Attention Deficit Hyperactivity Disorder (ADHD), but the nature of this relationship is not fully understood. A plausible explanation may be modification of the prefrontal cortical (PFC) dopamine system by epilepsy. Studies have shown that some children with ADHD have a less organized dopamine system, including a polymorphism in the DRD4 receptor. The current study investigated the effect of early onset seizures in the rat perinatal hypoxia model on the density of medial PFC receptors and performance of a sustained visual attention task in adulthood.Methods: Experimental subjects: Sprague Dawley and Long Evans rats were randomly assigned to either hypoxic or normoxic control treatment conditions. On postnatal day 10-12, animals were placed in an airtight chamber and, the O2 concentration was lowered to 5-7% and then continually lowered until the onset of apnea, then removed from the chamber. Control animals were placed in the chamber and maintained at normoxic conditions. Behavioral Testing: Three weeks after days after perinatal hypoxia or normoxia, animals were tested in a modified 5-arm maze for sustained visuospatial attention. In a series of phases, animals were trained to associate a light with either an escape route or a food reward. Trials became progressively more difficult with the delay and duration of the light stimulus randomized. The number of correct choices and latency to find the goal box was recorded for each trial. DRD4 Quantification: After transcardial perfusion between p60 and p100, brains were sectioned and incubated in: (1) Anti-NeuN, used to identify neurons; and (2) Anti- DRD4, used to identify D4 dopamine receptors Layers 2 and 3 of the medial PFC were imaged using a laser scanning confocal microscope. The density of DRD4 receptors to NeuN positive neurons was estimated in randomly positioned counting frames on three sections per animal. The total number of profiles in each counting frame was estimated using 3D reconstruction software.Results: Performance on the 5-arm maze task did not confirm the deficits in sustained attention that have been reported in some studies of human epileptic patients. In fact, when food was the motivating factor, rats in the perinatal hypoxia group outperformed control animals. Analysis of DRD4 immunopositive profiles did show a significant reduction in the DRD4 receptors in the medial PFC of adult rats in the perinatal hypoxia model that was independent of sex and strain.Conclusions: Early-life seizures in the rat produced by the perinatal hypoxia model causes long-term downregulation of dopamine DRD4 receptors in the medial PFC. Although this alteration did not correlate with impaired performance in the 5-arm maze task in this study, this receptor has been shown to correlate to sustained attention performance in rodents and humans, and may be a candidate mechanism in the comorbidity of epilepsy and attention disorders.