We have used limbic convulsions induced by systemic pilocarpine in rats combined with focal intracerebral injections concurrently to study the initiation and spread of seizure activity. Protection against pilocarpine-seizure development by antagonism of excitatory or facilitation of inhibitory neurotransmission at focal sites establishes the anatomical circuits involved in the propagation of seizures. The excitatory amino acid antagonist 2-amino-7-phosphonoheptanoate (APH, selective for the NMDA preferring glutamate receptor subtype) is potently anticonvulsant after bilateral focal injections into the habenula or mediodorsal thalamus. The dose of APH required to give sustained protection against pilocarpine-induced convulsions is 10 pmol for lateral habenula and 50 pmol for mediodorsal thalamus. The GABA agonist muscimol produces a similar sustained protection following focal injections (100 pmol/side) into either the lateral habenula or the mediodorsal thalamus. An overall decrease in the efferent neurotransmission of these two brain regions results in a strong anticonvulsant effect indicating their importance in modulating limbic seizure activity.