The substantia nigra (SN) is a critical site at which GABA agonist drugs act to exert anticonvulsant actions in a variety of experimental seizure models. We have recently discovered that the nigra-evoked protection against maximal electroshock seizures is abolished following removal of the superior colliculus (SC), indicating that nigrotectal projections may be crucial modulators of seizure susceptibility. We now intend to determine whether the role of SC in nigra-evoked anticonvulsant actions extends to other seizure models. Moreover, we will determine whether the integrity of SC is important for the actions of systemically administered anticonvulsant drugs. In addition, the specific region of SC (and the role of GABA within that region), important for nigra-evoked anticonvulsant actions, will be defined.
These aims will be accomplished by the use of intracerebral microinjections of drugs in combination with localized lesions in rat brain. In addition to SN, we have located another site at which GABA agonists act to exert an anticonvulsant action. This site is localized within the deep cortex and is capable of triggering bilaterally symmetrical convulsions in response to the unilateral application of picomole amounts of the GABA antagonist, bicuculline. We will further characterize this site pharmacologically in terms of both convulsant and anticonvulsant capabilities and investigate the relationship between this region and other brain regions including SN. In addition to GABAergic drugs, drugs influencing excitatory amino acid neurotransmission and certain neuroactive peptides (opioid and substance P analogs) will be investigated for their influence in the deep prepiriform cortex. Seizure activity will be evaluated both behaviorally and electrographically. The general goal is to investigate specific neural circuitry in the brain capable of controlling seizure susceptibility. We are interested in the way in which various brain regions and pathways interact to either induce or suppress the spread of convulsive activity. We will continue to identify anatomical sites of convulsant and anticonvulsant drug action. Characterization of the site at which drugs can act to control seizure propagation is important both for the understanding of mechanisms of seizure disorders as well as for the design of novel anticonvulsant therapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology A Study Section (NEUA)
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Georgetown University
Schools of Dentistry
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