Pharmacological and neurochemical evidence indicates that brain noradrenergic systems play an important role in the determination of audiogenic seizure severity in genetically
epilepsy-prone rats (GEPRs). In earlier studies, intracerebroventricular (ICV)
injections of
norepinephrine suppressed convulsions in a now extinct moderate seizure GEPR colony. Also, ICV noradrenergic agonists are known to produce dose-related
anticonvulsant effects in the extant moderate seizure GEPRs (GEPR-3s). The present experiments were undertaken to determine whether ICV
norepinephrine also suppresses audiogenic
seizures in the extant GEPR-3s and in the severe seizure genetically
epilepsy-prone rats (GEPR-9s).
Injections of
norepinephrine or vehicle were made into the lateral ventricle through implanted guides. GEPR-9s were pretreated systemically either with the
monoamine oxidase inhibitor pargyline or with saline. GEPR-3s received no pretreatment. In
pargyline pretreated GEPR-9s, seizure severity fell and the fraction of animals exhibiting an
anticonvulsant response increased progressively as the dose of
norepinephrine was increased. In saline pretreated GEPR-9s, the
anticonvulsant dose response curve for
norepinephrine was shifted to a higher dose range. Accordingly, the
anticonvulsant dose50 for
norepinephrine was significantly greater in saline pretreated GEPR-9s than in
pargyline pretreated animals. Moreover, the dose required to produce the
anticonvulsant effect in GEPR-9s was approximately 10 fold greater than in the earlier studies in the extinct moderate seizure GEPRs. Also, the current experiment with extent GEPR-3s, showed that ICV
norepinephrine was
anticonvulsant in the same dose that was effective in the extinct colony of moderate seizure GEPRs. In general terms, these observations provide additional evidence that noradrenergic influences are
anticonvulsant in the GEPR. The neurobiological factors responsible for reduced responsiveness of the GEPR-9 are presently unknown.