Regulation of epileptiform activity in hippocampus by nicotinic acetylcholine receptor activation

Abstract

Nicotinic acetylcholine receptors (nAChRs) regulate neuronal excitability within the CNS. To assess the possible modulatory influence of nAChRs on epileptiform activity, a range of nAChR ligands were applied during experimentally induced epileptiform activity in rat hippocampal slices. Bath application of the potassium channel blocker 4-aminopyridine (4AP; 10–50 μM) resulted in the development of spontaneous epileptiform bursting activity in area CA3 that consisted of short duration (257±15 ms) field events occuring regularly at a frequency of 0.4±0.02 Hz. Subsequent co-application of the selective nAChR agonists 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP; 0.3–300 μM), choline (0.01–3 mM) and lobeline (3–30 μM) produced sustained and concentration-dependent increases in burst frequency with maximal frequency potentiation of 37±5%, 27±5% and 24±11%, respectively. DMPP (10–30 μM; n=31) also potentiated epileptiform bursting induced by reducing GABA A receptor-mediated synaptic transmission using 20 μM bicuculline or enhancing NMDA receptor-mediated excitation by lowering extracellular Mg 2+. Irrespective of the epileptiform model studied all nAChR agonist induced frequency potentiation was reversed upon washout of the agonist or co-application of one of the selective nAChR antagonists dihydro-β-erythroidine (10–30 μM), mecamylamine (50–200 μM) or α-bungarotoxin (100 nM). These results provide compelling evidence that activation of nAChRs exacerbate epileptiform activity in the rat hippocampus.