General anaesthetics, such as etomidate, are thought to induce anaesthesia by enhancing inhibition within the nervous system. However, surprisingly little is known of their specific sites or mechanisms of action within the CNS. We have therefore investigated the effects of etomidate in a simple vertebrate system, the neural network controlling swimming in pre-feeding Xenopus laevis tadpoles (stages 37/8-42; Nieuwkoop & Faber, 1956). Bath application of R (+) etomidate (5-20 µM) had a strong, dose-dependent inhibitory effect on ventral root activity in immobilised animals, dramatically reducing: (i) swimming frequency (n = 14/14); (ii) the duration of episodes of fictive swimming (n = 12/14) and (iii) the duration of motor bursts (n = 7/7; larval preparations). These effects were substantially reversed by the GABA_A receptor antagonist bicuculline (20-40 µM), suggesting that R (+) etomidate potentiates the actions of GABA. Furthermore, the S (-) etomidate enantiomer (5-20 µM) had no effect on any of the parameters of swimming, even 20 min after application.

Intracellular recordings from presumed motor neurons in the spinal cord using KCl-filled electrodes, reveals two groups of spontaneous IPSPs during quiescent periods. These represent quantal release of GABA and glycine onto the recorded motor neuron. The two types of IPSP are easily distinguishable on the basis of their duration and their pharmacological sensitivity (Reith & Sillar, 1997). In the presence of R (+) etomidate (10-15 µM; n = 8), the duration of GABAergic potentials increased from around 90-200 ms in control to 450 ms-1 s under etomidate, while their frequency and amplitude remained unaffected. However, there was no change in the duration, amplitude or frequency of the glycinergic potentials. Subsequent addition of bicuculline, but not strychnine, abolished all of the GABAergic IPSPs. In the presence of TTX (1 µM; n = 4), R (+) etomidate was able to prolong the duration of the GABAergic IPSPs. There was no concomitant increase in the frequency or amplitude of either the GABAergic or glycinergic potentials, nor was there any change in membrane conductance or resting potential. Etomidate also had no obvious effects on either the excitatory or inhibitory (glycinergic) components of the synaptic drive during swimming. Taken together, these results suggest that etomidate is a selective and enantio-specific agonist at the GABA_A receptor. It is likely to be acting exclusively postsynaptically to prolong the effects of GABA at these receptors, in common with other classes of drugs with anaesthetic effects such as barbiturates.

This work was supported by the BBSRC and The Wellcome Trust.