Regulation of epileptiform activity in hippocampus by nicotinic acetylcholine receptor activation

Division of Neuroscience and Biomedical Systems, IBLS, University of Glasgow, Glasgow G12 8QQ, UK.
Epilepsy Research (Impact Factor: 2.02). 10/2003; 56(1):51-65. DOI: 10.1016/j.eplepsyres.2003.08.005
Source: PubMed


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.

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    ABSTRACT: Objective(s) Nicotinic acetylcholine receptors (nAChRs) regulate epileptiform activity and produce a sustained pro- epileptogenic action within the hippocampal slices. In the present study, we investigated the effect of nAChRs on evoked glutamatergic synaptic transmission in area CA3 and CA1 of rat hippocampal slices to identify possible excitatory circuits through which activation of nAChRs produce their pro-epileptogenic effects. Materials and Methods Hippocampal slices (400 µm thick) prepared in vitro from male Wistar rats (3-5 weeks), using standard procedures. Following 1 hr equilibration in artificial cerebrospinal fluid (ACSF), slices transferred to an interface recording chamber. Stimulatory electrodes placed within the hilus or Schaffer-collateral pathways and extracellular field recordings made in the stratum radiatum of the CA1 and CA3 regions to investigate evoked synaptic responses. Results Bath application of the selective nAChR agonist dimethylphenyl-piperanzinium (DMPP, 30 µM) resulted in a sustained and reversible enhancement of glutamate afferent evoked fEPSP amplitude by 15.7±5.1% (mean±SEM; n=8 of 12) in the CA3 region of the hippocampus but not in the CA1 (-5.25±8.3%, mean±SEM; n=5). Conclusion
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