The long term goal of this project is the elucidatin of cellular mechanisms of action of the anticonvulsant drugs, phenytoin and carbamazepine, which have similar utility in treatment of human seizure disorders.
Specific aims i nclude (1) identification of presynaptic, postsynaptic, and non-synaptic (direct membrane) actions of each drug; (2) determination of concentration-dependence of each action; (3) distinction between potential therapeutic and toxic actions by comparison of concentration-dependence and human clinical pharmacokinetic data; (4) differences if any, in concentration-dependence of specific actions on different types of neurons and, possibly, (5) testing of new anticonvulsant agents for concentration-dependence of actions on neurons in vitro. Electrophysiological techniques, including standard intracellular recording and iontophoresis, will be used to assay the pharmacological actions of the drugs on mouse cortical and spinal cord neurons in primary dissociated cell culture and on slices of hippocampus and neocortex of rat or mouse in vitro. Anticonvulsant mechanisms are incompletely understood despite empiric sucess of anticonvulsant therapy. Achievement of the above goals should enhance knowledge of how these drugs work, contribute to optimal use of available anticonvulsants, and possibly, lead to development of new drugs for the treatment of seizure disorders refractory to currently available agents.
