Abstracts

Neuronal nicotinic receptors modulate brain excitability and have recently been associated with at least one form of epilepsy. Additionally, several recent reports indicate that the genetic modification or deletion of nicotinic receptor genes in mice results in either increased or reduced thresholds for drug-induced seizures, depending upon which nicotinic receptor subtype has been modified or deleted. These results suggest that pharmacological manipulation of certain types of nicotinic receptors may be useful for treating some forms of epilepsy. Hippocampal slices were obtained from adult ([gt] 45 days old) male mice. Spontaneous bursting of the CA3 pyramidal neurons was induced either by tetanic stimulation of the CA3 recurrent collaterals or by GABA receptor blockade and measured using extracellular and whole-cell electrophysiological recordings. Once stable rates of bursting were established, the effects of nicotinic receptor-subtype selective ligands on CA3 bursting rates were determined. Preliminary results demonstrated that bath application of selective agonists of the [alpha]4[beta]2*-type nicotinic receptor reduced and in some cases stopped CA3 bursting. Conversely, bath application of the [alpha]7*-type nicotinic receptor selective agonist, choline, increased bursting rates. The mechanisms (ie, receptor activation or desensitization) by which nicotinic receptors modulate hippocampal excitability will be determined using pharmacological, genetic, and electrophysiological techniques. Preliminary data indicate that modulation of nicotinic receptor activity can result in dynamic modulation hippocampal excitability. Furthermore, these results suggest that nicotinic receptor systems could be exploited as novel targets for the treatment of at least some forms of epilepsy/seizure disorders. (Supported by the Epilepsy Foundation through the generous support of the American Epilepsy Society and the Milken Family Foundation (PD)and NS34700 (KS))