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.
