Anticonvulsant effects of intracerebroventricularly administered norepinephrine are potentiated in the presence of monoamine oxidase inhibition in severe seizure genetically epilepsy-prone rats (GEPR-9s).
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.
Mishra
P K
PK
Department of Basic Sciences, University of Illinois College of Medicine, Peoria 61656.
Kahle
E H
EH
Bettendorf
A F
AF
Dailey
J W
JW
Jobe
P C
PC
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage*; D004357:Drug Synergism; D004827:Epilepsy / Q000188:drug therapy / Q000503:physiopathology*; D005260:Female; D007276:Injections, Intraventricular; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage*; D009638:Norepinephrine / Q000008:administration & dosage*; D051381:Rats; D011922:Rats, Mutant Strains / Q000502:physiology*; D012640:Seizures / Q000188:drug therapy
D000927:Anticonvulsants; D008996:Monoamine Oxidase Inhibitors; D009638:Norepinephrine