The contribution of use-dependence to the actions of two novel antiepileptic drugs acting upon the GABA neurotransmitter system was investigated using the rat hippocampal slices preparation. The first study of this thesis demonstrated that tiagabine, a GABA uptake blocker, causes a more pronounced increase of GABAergic responses evoked by high-frequency stimulation (HFS) than of those elicited by a single stimulus. The predominant effect of tiagabine on HFS-evoked responses was to facilitate the generation of GABAA receptor-mediated depolarizations (DRs) which were capable of triggering bursts of action potentials when evoked from the stratum radiatum. / Since these results suggested that tiagabine may paradoxically promote rather than inhibit epileptiform discharges, the second study investigated the functional consequences of tiagabine-augmented DRs. Consistent with our observation of enhanced inhibition following HFS, the amplitude of evoked EPSPs superimposed upon tiagabine-augmented DRs were markedly reduced and could no longer trigger action potentials. A similar inhibitory effect on evoked EPSCs was also observed. The large conductance increase associated with the occurrence of DRs suggests that tiagabine can reduce the depolarizing influence of excitatory transmission by increasing the effectiveness of GABA-mediated shunting inhibition. / In the third study of this thesis, the effects of gamma-vinyl GABA (GVG, vigabatrin) were investigated in slices prepared from animals pretreated with either an anticonvulsant dose of GVG or saline. GVG pretreatment produced a frequency-dependent strengthening of GABA-mediated transmission such that repetitive stimulation at low-frequencies (2.5--10 Hz) was no longer associated with a depression of inhibition. A reduced sensitivity of evoked IPSCs to the actions of baclofen, a GABAB receptor agonist, suggests that GVG may have produced its frequency-dependent effects by depressing the efficacy of the GABA release regulating negative feedback mechanisms through the presynaptic GABAB autoreceptors. / In the final study of this thesis, the acute effects of bath applied GVG on GABAergic inhibition were examined. GVG (100--500 muM) caused a concentration-dependent disinhibitory effect which did not appear to be mediated through an antagonism of postsynaptic GABAA receptors. These results suggest that to acute actions of GVG, distinct from those mediated through is inactivation of GABA-T, do not contribute to the anticonvulsant properties of this drug. / In conclusion, to results presented suggest that both tiagabine and GVG produce use-dependent increases in inhibition, an effect which may importantly contribute to their anticonvulsant properties.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.37553 |
| Date | January 1998 |
| Creators | Jackson, Michael F. |
| Contributors | Capek, Radan (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology & Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001650393, proquestno: NQ50191, Theses scanned by UMI/ProQuest. |
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