The proposed research project is component of a broadly based effort to elucidate abnormalities responsible for the epilepsies. More specifically, the project is designed to determine the role of central nervous system noradrenergic transmission in the regulation of seizure predisposition in the genetically epilepsy-prone rat (GEPR). These animals have been chosen for this investigation partially because extensive data derived from their use provide an intriguing neurochemical foundation for our proposed studies. Also, the existing body of data suggests a high probability for a positive experimental outcome. Another major consideration persuaded us to select GEPRs as experimental outcome. Another major consideration persuaded us to select GEPRs as experimental subjects. These animals are attractive as a model of human epilepsy. The accumulating body of neurochemical evidence strongly supports the concept that brain noradrenergic deficits in the GEPR are partially responsible for the marked degree of seizure predisposition characteristic of these animals. Importantly, we now have data which provides clues for anatomically localizing the etiologically important noradrenergic terminal fields within the brain. The current project is designed to capitalize on this information. Discrete intracerebral neurotoxic lesions or pharmacologic treatments will be used to produce specific noradrenergic deficits or increments in terminal fields which are candidates for regulation of seizure predisposition in the GEPR. Once a noradrenergic alteration has been made, we will determine whether it causes changes in selected indices of seizure predisposition. The approaches to be utilized will enable us to identify the noradrenergic terminal fields which are responsible for epileptogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022672-04
Application #
3405393
Study Section
Neurology A Study Section (NEUA)
Project Start
1985-01-01
Project End
1991-11-30
Budget Start
1990-12-01
Budget End
1991-11-30
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
College of Medicine at Peoria
Department
Type
Schools of Medicine
DUNS #
City
Peoria
State
IL
Country
United States
Zip Code
61605
Wang, C; Mishra, P K; Dailey, J W et al. (1994) Noradrenergic terminal fields as determinants of seizure predisposition in GEPR-3s: a neuroanatomic assessment with intracerebral microinjections of 6-hydroxydopamine. Epilepsy Res 18:1-9
Jobe, P C; Mishra, P K; Browning, R A et al. (1994) Noradrenergic abnormalities in the genetically epilepsy-prone rat. Brain Res Bull 35:493-504
Mishra, P K; Burger, R L; Bettendorf, A F et al. (1994) Role of norepinephrine in forebrain and brainstem seizures: chemical lesioning of locus ceruleus with DSP4. Exp Neurol 125:58-64
Clough, R W; Browning, R A; Maring, M L et al. (1994) Effects of intraventricular locus coeruleus transplants on seizure severity in genetically epilepsy-prone rats following depletion of brain norepinephrine. J Neural Transplant Plast 5:65-79
Yan, Q S; Jobe, P C; Dailey, J W (1993) Thalamic deficiency in norepinephrine release detected via intracerebral microdialysis: a synaptic determinant of seizure predisposition in the genetically epilepsy-prone rat. Epilepsy Res 14:229-36
Mishra, P K; Kahle, E H; Bettendorf, A F et al. (1993) Anticonvulsant effects of intracerebroventricularly administered norepinephrine are potentiated in the presence of monoamine oxidase inhibition in severe seizure genetically epilepsy-prone rats (GEPR-9s). Life Sci 52:1435-41
Yan, Q S; Jobe, P C; Dailey, J W (1993) Noradrenergic mechanisms for the anticonvulsant effects of desipramine and yohimbine in genetically epilepsy-prone rats: studies with microdialysis. Brain Res 610:24-31
Ludvig, N; Mishra, P K; Yan, Q S et al. (1992) The paradoxical effect of NMDA receptor stimulation on electrical activity of the sensorimotor cortex in freely behaving rats: analysis by combined EEG-intracerebral microdialysis. Synapse 12:87-98
Dailey, J W; Yan, Q S; Mishra, P K et al. (1992) Effects of fluoxetine on convulsions and on brain serotonin as detected by microdialysis in genetically epilepsy-prone rats. J Pharmacol Exp Ther 260:533-40
Ludvig, N; Mishra, P K; Yan, Q S et al. (1992) The combined EEG-intracerebral microdialysis technique: a new tool for neuropharmacological studies on freely behaving animals. J Neurosci Methods 43:129-37

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