The six specific aims of this competing renewal are designed to determine the effects of anticonvulsant and convulsant drugs on ion-transport processes, acid-base homeostasis and electrophysiology of astrocytes in tissue culture. These studies are designed to test the hypothesis that anticonvulsants in addition to their effects on neurons and synapses also stimulate astrocytic regulatory processes, and in so doing provide the CNS with an enhanced ability to regulate electrolyte, acid-base and neurotransmitter homeostasis within the CNS, thereby limiting seizure activity. Specifically, primary cultures of mouse cerebral cortical astrocytes will be acutely and chronically exposed to therapeutic concentrations of the prototype anticonvulsants phenytoin, carbamazepine, valproate, diazepam, ethosuximide, acetazolamide, and to the calcium channel blocker flunarizine. The effects of the above treatments on; the uptake, steady-state distribution and release of 22 Na+, 42 K+, 36 Cl- and 45 Ca++; the intracellular concentration of Na+, K+, Cl- and H+; the transport enzymes Na+/K+, Ca++/Mg++ -ATPase and the glial specific enzyme carbonic anhydrase; the electrophysiology (membrane potential, resistance and conductance); and the uptake of the neurotransmitter substance glutamate will be assessed. In addition, studies to characterize the effect of the receptor specific convulsants N-methyl-d-aspartate, and entylenetetrazol on the above parameters in untreated and anticonvulsant-treated (acute and chronic) astrocytes will also be conducted. The focus of this application does not differ significantly from that of the initial grant. Such an analysis is important for if a thorough understanding of the mechanisms of these drugs is to be obtained, a comprehensive examination of their effects on astrocytes as well as neurons must be undertaken. These studies will also enhance our understanding of the seizure process. Thus, through an increased understanding of the mechanisms of the currently available anticonvulsant drugs and the processes underlying seizure disorders, drugs with greater selectively and fewer adverse effects can be developed.
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