Potentiation, activation and blockade of GABAA receptors of clonal murine hypothalamic GT1‐7 neurones by propofol

Abstract

The actions of GABA and the intravenous general anaesthetic propofol (2,6‐düsopropylphenol) on GABAA receptors of self‐replicating GT1‐7 hypothalamic neurones were investigated by the patch clamp technique. GABA (1 μm‐1 mM) dose‐dependently activated inward currents with an EC50 of 27 μm, recorded from whole cells voltage‐clamped at —60 mV. GABA (100 μm)‐activated currents reversed at the Cl− equilibrium potential. Propofol (0.1 −100 μm) dose‐dependently potentiated GABA (100 μm)‐evoked currents with an EC50 of 5 μm. In the absence of GABA, propofol (10 μm‐1 mM) activated small inward currents with a reversal potential similar to the CI− equilibrium potential. The peak current amplitudes activated by propofol were only 31% of those activated by GABA in the same cells. Like GABA (100 μm)‐activated currents, propofol (100 μm)‐activated currents were inhibited by the GABAA receptor antagonist, bicuculline (10 μm) and were abolished by Zn2+ (100 μm). Propofol (10, 30 and 100 μm) dose‐dependently activated currents in the absence of GABA. However, the peak amplitude of currents activated by propofol declined with concentrations > 100 μm. The cessation of application of a high dose of propofol (1 mM) was associated with a current ‘surge’. The surge current, seen after application of propofol (1 mM), had a reversal potential similar to the CI− equilibrium potential. The ratio between peak current amplitude in the presence of propofol (1 mM) and surge current amplitude after propofol application, were not dependent on holding potential. Thus, it is unlikely that the surge current represents reversal of a voltage‐dependent block of GABAA receptors by propofol. The amplitude of the surge current exceeded the amplitude of the initial propofol (1 mM)‐evoked current following brief applications, but declined after prolonged applications of the drug. The observed modulatory actions of propofol may be due to separate potentiation, activation and inhibitory sites for this anaesthetic agent on GT1‐7 cell GABAA receptors.