Alfaxalone potentiates and mimics GABA‐induced contractile responses in the guinea‐pig isolated ileum

Abstract

1 Alfaxalone (1-100nM) potentiated y-aminobutyric acidA (GABAA)-receptor-mediated contractile responses in the guinea-pig isolated ileum, with a leftward shift of the GABA concentrationresponse curve, and a significant potentiation of the GABA-induced contractions over the lower concentration-range for GABA (3-30pM). Alfadalone on the other hand, did not affect contractile responses to GABA.2 Picrotoxinin (1O yM) induced a non-parallel rightward shift of the GABA concentration-response curve, with a 50% depression of the maximum response to GABA. Alfaxalone (100 nM) potentiated the responses to GABA in the presence of picrotoxinin (1O yM) over the GABA concentration-range of 10-100 M, causing a leftward shift of the concentration-response curve, but without affecting the depression of the maximum response by picrotoxinin. 3 Bicuculline methochloride (10mM) caused a parallel rightward shift of the GABA concentrationresponse curve; the ratio of this shift was unchanged in the presence of alfaxalone (100MM), although the latter itself displaced the curve leftwards. 4 Alfaxalone (1-100mM) also induced a similar potentiation of contractile responses to 3-amino-1-propanesulphonic acid (3-APS), a GABA agonist not subject to uptake. Such concentrations of alfaxalone were ineffective against contractile responses to exogenous acetylcholine. 5 Higher concentrations of alfaxalone (1 pM and above), however, elicited a GABA-like ileal contraction, sensitive to both picrotoxinin (lO pM) and bicuculline (1O Mm). 6 In conclusion, alfaxalone potentiated GABAA-receptor-mediated contractile responses in the guinea-pig isolated ileum by acting at a modulatory site on GABAA-receptor-chloride-ionophore complexes of GABA-sensitive myenteric neurones, whilst high concentrations of alfaxalone exhibited a GABA-mimetic action at GABAA-receptors in the ileum. It is suggested that more than one site may exist where steroids interact with the GABAA-receptor-ionophore complexes.

Sex Differences in the Effects of Acute Swim Stress on Binding to GABAA Receptors in Mouse Brain

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Alphaxalone Activates a Cl− Conductance Independent of GABAA Receptors in Cultured Embryonic Human Dorsal Root Ganglion Neurons

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(+)‐Hydrastine, a potent competitive antagonist at mammalian GABAA receptors

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