Abstract

Intravenous GABAergic anesthetics are potent hypnotics but are rather ineffective in depressing movements. Immobility is mediated, in part, by the ventral horn of the spinal cord. We hypothesized that the efficacy of these anesthetics in producing immobility is compromised by the activation of GABA_A receptors located presynaptically, which modulate GABA release onto neurons in the ventral horn. Because anesthetics acting by modulation of GABA_A receptor function require GABA to be present at its binding site, a decrease in GABA release would abate their efficacy in reducing neuronal excitability. Here we report that in organotypic spinal cord slices, the efficacy of the intravenous anesthetic etomidate to depress network activity of ventral horn neurons is limited to approximately 60% at concentrations greater than 1 μM that produce immobility. Depression of spinal network activity was almost abolished in spinal slices from β3(N265M) knock-in mice. In the wild type, etomidate prolonged decay times of GABA_A receptor-mediated inhibitory postsynaptic currents (IPSCs) and concomitantly reduced the frequency of action potential-dependent IPSCs. Etomidate prolonged the decay time of GABA_A receptors at all tested concentrations. At concentrations greater than 1.0 μM, anesthetic-induced decrease of GABA release via modulation of presynaptic GABA_A receptors and enhancement of postsynaptic GABA_A receptor-function compensated for each other. The results suggest that the limited immobilizing efficacy of these agents is probably due to a presynaptic mechanism and that GABAergic agents with a specificity for post-versus presynaptic receptors would probably have much stronger immobilizing actions, pointing out novel avenues for drug development.