POSTOPERATIVE COGNITIVE DYSFUNCTION AND DELIRIUM Potentiation of GABAA receptor activity by volatile anaesthetics is reduced by a5GABAA receptor-preferring inverse agonists

Editor’s key points † Inhaled anaesthetics act by potentiating inhibitory type A GABA (GABAA) receptors to produce some of their desired, and perhaps undesired, effects. † Using cultured hippocampal neurones, inverse agonists selective for a5 subunit containing GABAA receptors reduced receptor potentiation by volatile anaesthetics. † Potentiation of a5 subunit-containing GABAA receptors might contribute to post-anaesthesia memory deficits, which might be reversible by selective inverse agonists. Background. Animal studies have shown that memory deficits in the early post-anaesthetic period can be prevented by pre-treatment with an inverse agonist that preferentially inhibits a5 subunit-containing g-aminobutyric acid type A (a5GABAA) receptors. The goal of this in vitro study was to determine whether inverse agonists that inhibit a5GABAA receptors reduce anaesthetic potentiation of GABAA receptor activity. Methods. Cultures of hippocampal neurones were prepared from Swiss white mice, wild-type mice (genetic background C57BL/6J and Sv129Ev) and a5GABAA receptor null mutant (Gabra52/2) mice. Whole-cell voltage clamp techniques were used to study the effects of the a5GABAA receptor-preferring inverse agonists L-655,708 and MRK-016 on anaesthetic potentiation of GABA-evoked currents.