Anticonvulsant effects of intracerebroventricularly administered norepinephrine are potentiated in the presence of monoamine oxidase inhibition in severe seizure genetically epilepsy-prone rats (GEPR-9s)

doi:10.1016/0024-3205(93)90067-D

Life Sciences

Volume 52, Issue 17, 1993, Pages 1435-1441

https://doi.org/10.1016/0024-3205(93)90067-D Get rights and content

Abstract

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, intracerebro-ventricular (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 seizure 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 extant 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.

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Extensive evidence supports the regulatory role of NADergic neurotransmission in the control of seizure susceptibility, including seizure propagation in the limbic structures [52,53]. Genetically epilepsy-prone rats (GEPR), in which the NADergic system has been disturbed, are more sensitive to experimentally evoked seizures, and restoration of NADergic activity has been shown to attenuate the enhanced seizure susceptibility [54,55]. Moreover, activation of the locus coeruleus NADergic system [56] and hippocampal NAD reuptake inhibition [57] is able to alleviate seizure activity induced by chemoconvulsants.
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Anticonvulsant effects of intracerebroventricularly administered norepinephrine are potentiated in the presence of monoamine oxidase inhibition in severe seizure genetically epilepsy-prone rats (GEPR-9s)

Abstract

Life Sci.

Epilepsy Res.

Epilepsy Res.

Brain Res.

Epilepsy Research

Brain Res.

Drugs for the Control of Epilepsy: Action of Neuronal Networks Involved in Seizure Disorders

Concepts and Models in Epilepsy Reseach

Epilepsia

Epilepsia

Epilepsy Res.

J. Pharmacol. Exp. Ther.

The FASEB Journal

Experientia