Patten, Debra (1999) An electrophysiological study of the interaction between fenamate NSAIDs and the GABA(_A) receptor. Doctoral thesis, Durham University.
The effects of certain NSAIDs were determined on agonist-evoked responses recorded from rat neurones maintained in vitro using electrophysiological techniques. Initially, the rat isolated vagus and optic nerves were employed. Alphaxalone, pentobarbitone, propofol and the NSAID, mefenamic acid (MFA), potentiated GABA-evoked responses of the vagus nerve. Propofol (1-100µM) selectively potentiated GABA and glycine-evoked responses of the rat vagus and optic nerves, but had little effect on nicotinic acetylcholine-, a,β-methylene-ATP or 5-hydroxytryptamine-mediated responses. The interaction between MFA and ligand-gated receptors was investigated further using voltage-clamped rat hippocampal neurones maintained in culture. MFA (3-100µM) selectively, concentration-dependently and reversibly potentiated GABA-evoked responses, consistent with the observations made using the vagus nerve. MFA (3-100|aM) however had little or no effect on glycine, AMPA, kainate or NMDA-receptor mediated responses. A final series of experiments investigated the site and molecular mechanism of the interaction between MFA and the GABA-gated chloride ion channel. The potentiating effects of MFA (and other fenamates) were not the result of prostaglandin synthesis inhibition, since other NSAIDs did not modulate the GABA(_A) receptor (GR). The actions of MFA were not mediated via the benzodiazepine site of the GR, nor where they due to inhibition of GABA- uptake or membrane perturbation. The modulatory effects of MFA were not use-dependent, but the potentiating effects of MFA were voltage-dependent, where the potentiation was 3-fold greater at -100mV than at +40mV, with no change in the equilibrium potential for GABA. MFA activated a current, in the absence of GABA. Hippocampal neurones varied in sensitivity to modulation by MFA and the anticonvulsant, loreclezole, which may indicate a degree of sub- unit selectivity. These data are discussed in relation to the possible site and mechanism of action of fenamates at the GR, their similarities with other positive modulators of the GR and the neurophysiological implications of these findings.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||13 Sep 2012 15:47|