title: 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 microM) resulted in the development of spontaneous epileptiform bursting activity in area CA3 that consisted of short duration (257+/-15 ms) field events occurring 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 microM), choline (0.01-3mM) and lobeline (3-30 microM) 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 microM; n=31) also potentiated epileptiform bursting induced by reducing GABA(A) receptor-mediated synaptic transmission using 20 microM 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-beta-erythroidine (10-30 microM), mecamylamine (50-200 microM) or alpha-bungarotoxin (100 nM). These results provide compelling evidence that activation of nAChRs exacerbate epileptiform activity in the rat hippocampus.
authors.affiliation: Division of Neuroscience and Biomedical Systems, IBLS, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: S
authors.initials: S
authors.lastname: Roshan-Milani
authors.forename: L
authors.initials: L
authors.lastname: Ferrigan
authors.forename: M J
authors.initials: MJ
authors.lastname: Khoshnood
authors.forename: C H
authors.initials: CH
authors.lastname: Davies
authors.forename: S R
authors.initials: SR
authors.lastname: Cobb
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D015761:4-Aminopyridine; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001640:Bicuculline; D002794:Choline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004594:Electrophysiology / Q000379:methods; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000502:physiology*; D012044:Regression Analysis
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D015763:2-Amino-5-phosphonovalerate; D015761:4-Aminopyridine; D002794:Choline; D001640:Bicuculline