Propofol regulates arousal by enhancing inhibitory synaptic transmission of noradrenergic neurons in the locus coeruleus of adult male mice

Locus coeruleus-noradrenergic (LC-NA) neurons have been suggested to be involved in the effects of general anesthetics. However, the contribution of LC-NA neurons during propofol anesthesia remains unknown. We aimed to elucidate the mechanism of action of propofol in the LC-NA neurons. LC-NA neurons from adult male mice were identified by targeted expression of fluorescent proteins. Whole-cell patch-clamp recordings were performed to analyze the effects of propofol on action potentials and synaptic transmission. The results showed that propofol induced a concentration-dependent reduction in action potential firing frequency. It also increased the frequency of spontaneous inhibitory postsynaptic currents and prolonged their decay time. The presence of GABA_A receptor antagonist bicuculline prevented these effects. Inhibitory tonic currents were evoked only at high concentrations of propofol. In behavioral experiments, bicuculline injection into the LC significantly shortened the return of righting reflex time following propofol anesthesia. We demonstrated that clinically relevant doses of propofol facilitated phasic GABAergic neural currents and acted directly on GABA_A receptors in LC-NA neurons. Enhanced GABA_A receptor-mediated inhibition in LC-NA neurons likely underlies the anesthetic mechanism of propofol. Whereas previous studies emphasized tonic inhibition as the major mechanism of propofol action, our findings demonstrate that phasic inhibition predominates at clinically relevant concentrations.