Regulation of epileptiform activity in hippocampus by nicotinic acetylcholine receptor activation

• Published in: Epilepsy research 2003-09, Vol.56 (1), p.51-65
• Main Authors: Roshan-Milani, S., Ferrigan, L., Khoshnood, M.J., Davies, C.H., Cobb, S.R.
• Format: Article
• Language: English
• Subjects: 2-Amino-5-phosphonovalerate - pharmacology; 4-Aminopyridine; Acetylcholine; Action Potentials - drug effects; Action Potentials - physiology; Analysis of Variance; Animals; Bicuculline; Biological and medical sciences; Choline - pharmacology; Dose-Response Relationship, Drug; Drug Interactions; Electrophysiology - methods; Epilepsy; Epilepsy - chemically induced; Epilepsy - physiopathology; Excitatory Amino Acid Antagonists - pharmacology; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hippocampus; Hippocampus - drug effects; Hippocampus - physiopathology; In Vitro Techniques; Male; Medical sciences; Nervous system (semeiology, syndromes); Neurology; Nicotinic; Nicotinic Agonists - pharmacology; Nicotinic Antagonists - pharmacology; Rats; Rats, Wistar; Receptors, Nicotinic - physiology; Regression Analysis
• ISSN: 0920-1211; 1872-6844
• DOI: 10.1016/j.eplepsyres.2003.08.005

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.