Noradrenergic terminal fields as determinants of seizure predisposition in GEPR-3s: a neuroanatomic assessment with intracerebral microinjections of 6-hydroxydopamine.

The genetically epilepsy-prone rat (GEPR) and other mammals with genetically based epilepsy are characterized by an innate predisposition to seizures evoked by a wide variety of stimuli (including those of endogenous origin). The present investigation was undertaken to identify the anatomical location of the noradrenergic terminal fields responsible for regulation of seizure predisposition. In this study, audiogenic seizure severity was used as the index of seizure predisposition. The effect of widespread destruction of noradrenergic terminal fields was compared with the effect of destroying regionally distinct terminal fields. These lesions were produced by microinfusion of 6-hydroxydopamine (6-OHDA) into the locus ceruleus, the A1 noradrenergic area, the noradrenergic dorsal bundle, the cerebellar peduncles and spinal intrathecal space. Selective depletion of norepinephrine in the forebrain, the cerebellum, or the spinal cord failed to alter audiogenic seizure severity. An increase in seizure severity was always associated with marked depletion of norepinephrine in the midbrain excluding the inferior colliculus. Also a significant correlation existed between the seizure intensification and reduction of norepinephrine in this structure in all instances where a seizure intensification was observed. An association of seizure intensification also existed in all cases except one with depletion in the pons/medulla. The present findings support the hypothesis that the noradrenergic terminal fields of the midbrain excluding the inferior colliculus are determinants of seizure predisposition. Inasmuch as audiogenic seizures are a type of brainstem seizure, the present findings do not a priori pertain to the noradrenergic regulation of forebrain seizures.