Zhong, Yu; (1997) Allosteric modulation of GABAA receptors by steroids and related compounds: functional and binding studies. Doctoral thesis (Ph.D), UCL (University College London).

Text Allosteric_modulation_of_GABAA.pdf Download (4MB)

Abstract

The allosteric modulation of GABAA receptors by neuroactive steroids and related compounds was investigated, using 3H-flunitrazepam binding to synaptic membranes prepared from rat whole brain and electrophysiological recording from rat cuneate nucleus in a grease-gap apparatus. The enhancement of 3H-flunitrazepam binding by pregnanolone, a reduced metabolite of progesterone, involves GABA-dependent and GABA-independent components. A low affinity component of pregnanolone's action is selectively antagonised by 11-ketoprogesterone. However, progesterone itself antagonises both high and low affinity components with only a slight selectivity against the low affinity component. Piegnenolone, the precursor of progestelone, has no effect while epipregnanolone, the 3β analogue of pregnanolone, causes a small general depression of the effects of pregnanolone. The properties described above strongly suggest multiple binding sites for pregnanolone on GABA A receptors. The binding sites for pregnanolone are separate from those for propofol, which enhances 3H-flunitrazepam binding in a largely GABA-independent manner that is not sensitive to 11-ketoprogesterone. The enhancement of 3H-flunitrazepam binding by Δ 16- alphaxalone is quite different from the enhancement by pregnanolone and propofol. It is GABA-dependent, with similar potency and efficacy to alphaxalone, but less potent and much less efficacious than pregnanolone. However, the interactions between pairs of steroids when used in combination suggest that Δ 16-alphaxalone may share the same range of binding sites as pregnanolone and alphaxalone. Compared with chlormethiazole and pentobaibitone, loreclezole is the most efficacious enhancer of 3H-flunitiazepam binding. The enhancement by loreclezole is due to an increase in binding affinity, is largely GABA-independent and can be partially blocked by chlormethiazole. However, chlormethiazole and pentobarbitone are more efficacious than loreclezole in potentiating responses to muscimol in cuneate nucleus slices. The interactions among loreclezole, chlormethiazole and pentobarbitone suggest separate sites of action for them on the GABAA receptor complex.

Download activity - last month

Export as JSONXMLCSV

Download activity - last 12 months

Export as CSVXMLJSON

Downloads by country - last 12 months

Export as CSVJSONXML

Archive Staff Only

View Item