This project will test the hypothesis that generalized seizures are mediated by specific regions of the mammalian thalamus and will define such regions and characterize their role. This will be done by determining the effects of discrete thalamic lesions and microinjection of neuroactive substances which affect major inhibitory or excitatory neurotransmitter systems on the threshold doses for seizures and electroencephalographic discharges occurring during timed continuous intravenous infusion of the convulsant drug pentylenetetrazol. Following the delineation of the thalamic areas which regulate these seizures, the electrophysiological activity of these regions will be characterized and correlated with the behavioral and EEG events occurring during pentylenetetrazol infusion. Finally, the effects of microinjection of a variety of neurotransmitter substances or their agonist or antagonists on local thalamic electrophysiological activity, electrocortical activity, spontaneous behavior and seizures will be examined. The compounds to be studies will include agents acting on receptors known to be present in high concentrations in the identified thalamic regions and substances with known pro- and anticonvulsant actions. Elucidating the thalamic substrate regulating seizures not only would provide greater understanding of the basic processes of human generalized epilepsy, but also would have relevance to the study and development of antiepileptic drugs, since identification of the site of action of these drugs is a prerequisite for understanding their mechanism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS001296-03
Application #
3084188
Study Section
Neurological Disorders Program Project Review B Committee (NSPB)
Project Start
1988-08-01
Project End
1991-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Miller, J W; Gray, B C; Bardgett, M E (1992) Effects of selective toxic lesions of cholinergic neurons of the laterodorsal tegmental nucleus on experimental seizures. Brain Res 579:161-4
Miller, J W; Gray, B C; Bardgett, M E (1992) Characterization of cholinergic regulation of seizures by the midline thalamus. Neuropharmacology 31:349-56
Miller, J W (1992) The role of mesencephalic and thalamic arousal systems in experimental seizures. Prog Neurobiol 39:155-78
Miller, J W; Bardgett, M E; Gray, B C (1991) The role of the laterodorsal tegmental nucleus of the rat in experimental seizures. Neuroscience 43:41-9
Miller, J W; Ferrendelli, J A (1990) Characterization of GABAergic seizure regulation in the midline thalamus. Neuropharmacology 29:649-55
Miller, J W; Ferrendelli, J A (1990) The central medial nucleus: thalamic site of seizure regulation. Brain Res 508:297-300
Miller, J W; Hall, C M; Holland, K D et al. (1989) Identification of a median thalamic system regulating seizures and arousal. Epilepsia 30:493-500