The 2 goals of the proposed research are to determine if: (1) systemically administered glycine potentiates the activity of anticonvulsant drugs in experimental models of epilepsy; (2) the glycine potentiation is mediated by a GABAergic mechanism in the substantia nigra. The first goal will be accomplished by determining the effect of orally administered glycine on the anticonvulsant and neurotoxic activity of anticonvulsant drugs effective in experimental models of grand mal (maximal electroshock), petit mal (s.c. pentylenetetrazol) and psychomotor (kindled amygdaloid seizures) epilepsy. Because the glycinergic potentiation might result from pharmacokinetic interactions, successful glycine-anticonvulsant combinations will be tested to determine the effects of the co- administration on glycine and anticonvulsant drug distribution in brain and serum.
The second aim i s to be accomplished using microinjection techniques to determine if localized substantia nigra infusions of glycine potentiate systemically administered anticonvulsants in the same 3 models of epilepsy. Experiments combining the microinjection of GABA agonists and glycine will establish if the glycine activity in the nigra is a result of an interaction with GABA. Combined strychnine and glycine microinjection will determine if the glycine activity is due to a specific, receptor mediated effect. This project will identify anticonvulsant therapies for specific epilepsies that may benefit from the adjunctive use of glycine. Since glycine appears to be non-toxic in humans, it may be that the addition of glycine will allow the reduction of the anticonvulsant dose, thereby decreasing the drug induced toxicity without sacrificing effectiveness. The results will also contribute to the understanding of the role of glycine in the mechanisms of convulsions and the neuropharmacology of anticonvulsant drugs, particularly in relation to GABA mechanisms in the substantia nigra.
