Investigation of the role of nicotinic acetylcholine receptors in modulating epileptiform activity

Roshan-Milani, Shiva (2004) Investigation of the role of nicotinic acetylcholine receptors in modulating epileptiform activity. PhD thesis, University of Glasgow.

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Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that have been implicated in a variety of brain functions as well as pathological states. In the Mppocampus, nAChRs appear to modulate both excitatory and inhibitory circuits. The numerous subunits that make up nAChRs result in a great diversity of functional receptors, equipping them with different pharmacological and biophysical properties. It has recently been found that certain forms of epilepsy may arise from mutation in the genes responsible for encoding of nAChR subunits. Moreover, many reports have shown that high doses of nicotine induce seizures in animals, which are blocked by different nAChR antagonists. However, the mechanism underling the role of nAChRs in patterning epileptiform activity is poorly understood. This project aims to establish the role that nAChRs may play in experimental models of epilepsy and to assess whether pharmacological agents acting at these receptors might represent a novel avenue for developing future anticonvulsants. To assess the possible modulatory influence of nAChRs on epileptiform activity, a range of nAChR ligands were applied during experimentally induced epileptiform activity in hippocampal slices prepared from wistar rats (2-6 weeks). Extracellular recordings were obtained in the stratum pyramidale of the area CAS (n=280). Initial experiments investigated the effects of nAChR ligands on 4-aminopyridine (4AP)-induced epileptiform activity. The work presented in the rest of the thesis was focused to establish the mechanisms by which nAChRs mediate their pro-epileptogenic actions. This study demonstrates that nAChRs regulate epileptiform discharges generated by a number of different pharmacological manipulations. The cellular mechanisms generating each pattern of epileptiform activity are quite distinct involving complex interactions between synaptic and non-synaptic elements of different neuronal circuits. Since nAChRs produce a similar phenotype of modulation in each epileptiform model it is possible that nAChRs target a common cellular mechanism that is prevalent in each model and which mediates the increase in burst frequency in these models.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Cobb, Dr Stuart
Date of Award: 2004
Depositing User: Mrs Monika Milewska-Fiertek
Unique ID: glathesis:2004-30950
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 25 Oct 2018 09:19
Last Modified: 09 Aug 2021 15:30
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