Noradrenergic and serotonergic determinants of seizure susceptibility and severity in genetically epilepsy-prone rats

Pharmacological studies demonstrate a reciprocal relationship between both noradrenergic and serotonergic transmission and audiogenic seizure severity and susceptibility in the genetically epilepsy-prone rat (GEPR). In contrast, drug-induced changes in the neurochemical indices of dopaminergic activity do not result in alterations in seizure severity. These pharmacological investigations led to the hypothesis that both noradrenergic and serotonergic neurons are capable of regulating seizure severity in the GEPR. Pharmacological investigations also provided evidence that monoaminergic neurons serve as determinants of seizure susceptibility in these epileptic animals. The GEPR is susceptible to environmentally-induced seizures which cannot be precipitated in neurologically normal subjects. Drug studies suggest that monoaminergic decrements serve as one set of susceptibility determinants. However, non-monoaminergic abnormalities also play important roles in the seizure predisposition which characterizes the GEPR. Pathophysiological studies have confirmed and extended the concepts generated by the pharmacological investigations. Noradrenergic and serotonergic deficits do indeed characterize the seizure naive state of the GEPR. These studies have provided a basis for tentative identification of areas of the brain in which monoaminergic abnormalities regulate seizure severity and susceptibility. Monoaminergic defects in some areas such as the thalamus may regulate both susceptibility and severity. In other areas, defects may regulate only severity or susceptibility. In the striatum, noradrenergic defects do not appear to be present and probably are not determinants of the epileptic state of the GEPR.