Potentiation of GABAA receptor activity by volatile anaesthetics is reduced by α5GABAA receptor-preferring 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 α5 subunit-containing γ-aminobutyric acid type A (α5GABA(A)) receptors. The goal of this in vitro study was to determine whether inverse agonists that inhibit α5GABA(A) 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 α5GABA(A)receptor null mutant (Gabra5-/-) mice. Whole-cell voltage clamp techniques were used to study the effects of the α5GABA(A) receptor-preferring inverse agonists L-655,708 and MRK-016 on anaesthetic potentiation of GABA-evoked currents.

RESULTS: L-655,708 (50 nM) reduced sevoflurane potentiation of GABA-evoked current in wild-type neurones but not Gabra5-/- neurones, and produced a rightward shift in the sevoflurane concentration-response plot [sevoflurane EC50: 1.9 (0.1) mM; sevoflurane+L-655,708 EC(50): 2.4 (0.2) mM, P<0.05]. Similarly, L-655,708 (50 nM) reduced isoflurane potentiation of GABA-evoked current [isoflurane: 4.0 (0.6) pA pF(-1); isoflurane+L-655,708: 3.1 (0.5) pA pF(-1), P<0.01]. MRK-016 also reduced sevoflurane and isoflurane enhancement of GABA-evoked current [sevoflurane: 1.5 (0.1) pA pF(-1); sevoflurane+MRK-016 (10 nM): 1.2 (0.1) pA pF(-1), P<0.05; isoflurane: 3.5 (0.3) pA pF(-1); isoflurane+MRK-016 (1 nM): 2.9 (0.2) pA pF(-1), P<0.05].

CONCLUSIONS: L-655,708 and MRK-016 reduced the potentiation by inhaled anaesthetics of GABAA receptor activated by a low concentration of GABA. Future studies are required to determine whether this effect contributes to the memory preserving properties of inverse agonists after anaesthesia.